Compounds as pharmaceutical agents

ABSTRACT

The current invention relates to compounds of the formula: (Ia) and the pharmaceutically acceptable salts thereof and their use as TGF-beta signal transduction inhibitors for treating cancer and other diseases in a patient in need thereof by administration of said compounds.

The invention relates to new compounds and their use as pharmaceuticalagents, in particular their use as TGF-beta signal transductioninhibitors.

BACKGROUND OF THE INVENTION

The transforming growth factor-beta (TGF-beta) (“TGF-β3”) polypeptidesinfluence growth, differentiation, and gene expression in many celltypes. The first polypeptide of this family that was characterized,TGF-β1, has two identical 112 amino acid subunits that are covalentlylinked. TGF-β3, is a highly conserved protein with only a single aminoacid difference distinguishing humans from mice. There are two othermembers of the TGF-β3 gene family that are expressed in mammals. TGF-β2is 71% homologous to TGF-β1 (de Martin, et al. (1987) EMBO J.6:3673-3677), whereas TGF-β3 is 80% homologous to TGF-β1 (Derynck, etal. (1988) EMBO J. 7:3737-3743). There are at least three differentextracellular TGF-β receptors, Type I, II and III that are involved inthe biological functions of TGF-β1, -β2 and -β3 (For reviews, seeDerynck (1994) TIBS 19:548-553 and Massague (1990) Ann. Rev. Cell Biol.6:597-641). The Type I and Type II receptors are transmembraneserine/threonine kinases that in the presence of TGF-β form aheteromeric signaling complex (Wrana, et al (1992) Cell 71: 1003-1014).

The mechanism of activation of the heteromeric signaling complex at thecell surface has been elucidated (Wrana, et al. (1994) Nature 370:341-347). TGF-β3 first binds the type II receptor that is aconstitutively active transmembrane serine/threonine kinase. The type Ireceptor is subsequently recruited into the complex, phoshorylated atthe GS domain and activated to phosphorylate downstream signalingcomponents (e.g. Smad proteins) to initiate the intracellular signalingcascade. A constitutively active type I receptor (T204D mutant) has beenshown to effectively transduce TGF-β responses, thus bypassing therequirement for TGF-β and the type II receptor (Wieser, et al. (1995)EMBO J. 14: 2199-2208). Although no signaling function has beendiscovered for the type III receptor, it does increase the affinity ofTGF-β2 for the type II receptor making it essentially equipotent withTGF-β1 and TGF-β3 (Lopez-Casillas, et al. (1993) Cell 73: 1435-1444).

Vascular endothelial cells lack the Type III receptor. Insteadendothelial cells express a structurally related protein called endoglin(Cheifetz, et al. (1992) J. Biol. Chem. 267:19027-19030), which onlybinds TGF-β1 and TGF-β3 with high affinity. Thus, the relative potencyof the TGF-β's reflects the type of receptors expressed in a cell andorgan system. In addition to the regulation of the components in themulti-factorial signaling pathway, the distribution of the synthesis ofTGF-β polypeptides also affects physiological function. The distributionof TGF-β2 and TGF-β3 is more limited Derynck, et al. (1988) EMBO J.7:3737-3743) than TGF-β1, e.g., TGF-β3 is limited to tissues ofmesenchymal origin, whereas TGF-β1 is present in both tissues ofmesenchymal and epithelial origin.

TGF-β1 is a multifunctional cytokine critical for tissue repair. Highconcentrations of TGF-β1 are delivered to the site of injury by plateletgranules (Assoian and Sporn (1986) J. Cell Biol. 102:1217-1223). TGF-β1initiates a series of events that promote healing including chemo taxisof cells such as leukocytes, monocytes and fibroblasts, and regulationof growth factors and cytokines involved in angiogenesis, cell divisionassociated with tissue repair and inflammatory responses. TGF-β1 alsostimulates the synthesis of extracellular matrix components (Roberts, etal. (1986) Proc. Natl. Acad. Sci. USA 83:4167-4171; Sporn, et al. (1983)Science 219:1329-1330; Massague (1987) Cell 49:437-438) and mostimportantly for understanding the pathophysiology of TGF-β1, TGF-β1autoregulates its own synthesis (Kim, et al. (1989) J. Biol. Chem.264:7041-7045).

The compounds disclosed herein may also exhibit other kinase activity,such as p38 kinase inhibition and/or KDR (VEGFR2) kinase inhibition.Assays to determine such kinase activity are known in the art and oneskilled in the art would be able to test the disclosed compounds forsuch activity.

The compounds disclosed and claimed in this patent application aregenerally related to compounds disclosed and claimed in PCT patentapplication number PCT/US002/11884, filed 13 May 2002, which claimspriority from U.S. patent application U.S. Ser. No. 60/293,464, filed 24May 2001, and is herein incorporated by reference.

SUMMARY OF THE INVENTION

A compound of the formula:

wherein n is 1-4;

R₁ may be one or more optional substituents selected from the groupconsisting of: (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,(C1-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C1-C6)alkylthio,(C1-C6)alkylsulphinyl, (C1-C6)alkylsulphonyl, (C₁-C6)alkylamino,di-[(C1-C6)alkyl]amino, (C1-C6)alkoxycarbonyl, N-(C1-C6)alkylcarbamoyl,N,N-di-[(C1-C6)alkyl]carbamoyl, (C2-C6)alkanoyl, (C2-C6)alkanoyloxy,(C2-C6)alkanoylamino, N-(C1-C6)alkyl-(C2-C6)alkanoylamino,(C3-C6)alkenoylamino, N-(C1-C6)alkyl-(C3-C6)alkenoylamino,(C3-C6)alkynoylamino, N-(C1-C6)alkyl-(C3-C6)alkynoylamino,N-(C1-C6)alkylsulphamoyl, N,N-di-[(C₁-C6)alkyl]sulphamoyl,(C1-C6)alkanesulphonylamino, N-(C1-C6)alkyl-(C1-C6)alkanesulphonylamino,carboxamide, ethylene, thiophenyl, aminophenyl, trifluoromethyl, halo,trifluoromethoxy, hydroxymethyl, N-pyrrolidino, N-morpholino,phenylthio, (C1-C4)dialkylaminomethyl, methoxyphenyl, amino, hydroxy,carboxyl, phenyl, arylalky;

R₂ is selected from the group comprising unsubstituted or substitutedthiophene; unsubstituted or substituted oxazole; unsubstituted orsubstituted pyrazine; unsubstituted or substitutedpyrido[2,3-b]pyrazine; unsubstituted or substituted furan; unsubstitutedor substituted imidazo[1,2-a]pyridine; unsubstituted or substitutedbenzoimidazole; unsubstituted or substituted quinoxaline; unsubstitutedor substituted quinoxaline-2-one; unsubstituted or substitutedisoquinoline; unsubstituted or substituted benzothiazole; unsubstitutedor substituted indole; unsubstituted or substitutedimidazo[4,5-b]pyridine; unsubstituted or substitutedimidazo[4,5-c]pyridine; unsubstituted or substitutedoxazolo[4,5-b]pyridine; unsubstituted or substituted dihydrobenzofuran;unsubstituted or substituted benzofuran; unsubstituted or substitutedbenzo[2,1,3]thiadiazole; unsubstituted or substitutedbenzo[1,2,5]thiadiazole; unsubstituted or substitutedpyrazolo[1,5-a]pyrimidine; unsubstituted or substituted3,4-dihydro-2H-benzo[b][1,4]dioxepine; unsubstituted or substituted[1,5]naphthyridine; unsubstituted or substituted [1,6]naphthyridine; orunsubstituted or substituted [1,8]naphthyridine;

wherein the substitution may independently be one or more of thefollowing: (C1-C6)alkyl; (C1-C6)alkoxy; halogen; hydroxy; nitro; amino;

phenyl or substituted phenyl, wherein the phenyl may independently besubstituted by one or two of the following: halogen, (C1-C6)alkyl,(C1-C6)alkoxy, nitro, amino, or hydroxy;

-   —(CH₂)_(m)R⁸;-   —(CH₂)_(o)(O)R⁹;-   —(CH₂)_(o)C(O)morpholine;-   —C(O)R⁶;-   —C(O)OR⁴;-   —C(O)NR⁴R⁵;-   —C(O)NR⁴(CH₂)_(o)NR₄R⁵;-   —NR⁴(C1-C9)alkyl;-   —NR⁴C(O)(CH₂)_(m)CH₃-   —NR⁴C(O)(CH₂)_(o)NR⁴R⁵;-   —O(CH₂)_(o)R⁷;-   or —OC(O)R⁴;    wherein-   m is 0, 1, 2 or 3;-   o is 1, 2 or 3;-   R⁴ and R⁵ are each independently hydrogen or (C1-C6)alkyl;-   R⁶ is hydrogen, (C1-C6)alkyl or —NR⁴R⁵;-   R⁷ is hydroxy, cyano, pyrrolidine or NR⁴R⁵;-   R₈ is morpholine, hydroxy, pyrrolidine, tetrahydropyran,    (C1-C6)alkyl or NR₄R⁵;-   R⁹ is morpholine, pyrrolidine, tetrahydropyran, or (C1-C6)alkyl;

R₃ is hydrogen or (C1-C6)alkyl;

and the pharmaceutically acceptable salts thereof.

A more preferred embodiment of the invention are compounds of theformula:

wherein n is 0 or 1;

-   R₁ is hydrogen or (C1-C4alkyl);

R₂ is selected from the group comprising unsubstituted or substitutedthiophene; unsubstituted or substituted oxazole; unsubstituted orsubstituted pyrazine; unsubstituted or substituted faran; unsubstitutedor substituted imidazo[1,2-a]pyridine; unsubstituted or substitutedbenzoimidazole; unsubstituted or substituted quinoxaline; unsubstitutedor substituted isoquinoline; unsubstituted or substituted benzothiazole;unsubstituted or substituted indole; unsubstituted or substitutedimidazo[4,5-b]pyridine; unsubstituted or substitutedimidazo[4,5-c]pyridine; unsubstituted or substitutedoxazolo[4,5-b]pyridine; unsubstituted or substituted dihydrobenzofuran;unsubstituted or substituted benzofuran; unsubstituted or substitutedbenzo[2,1,3]thiadiazole; unsubstituted or substitutedbenzo[1,2,5]thiadiazole; unsubstituted or substitutedpyrazolo[1,5-a]pyrimidine; unsubstituted or substituted3,4-dihydro-2H-benzo[b][1,4]dioxepine; unsubstituted or substituted[1,5]naphthyridine; unsubstituted or substituted [1,6]naphthyridine; orunsubstituted or substituted [1,8]naphthyridine;

wherein the substitution may independently be one or more of thefollowing: (C1-C6)alkyl; (C1-C6)alkoxy; halogen; hydroxy; nitro; amino;

phenyl or substituted phenyl, wherein the phenyl is substituted by oneor two halogens;

-   —(CH₂)_(m)R⁸;-   —(CH₂)_(o)(O)R⁹;-   (CH₂)_(o)C(O)morpholine;-   —C(O)R⁶;-   —C(O)OR⁴;-   —C(O)NR⁴R⁵;-   —C(O)NR⁴(CH₂)_(o)NR₄R⁵;-   —NR⁴(C1-C9)alkyl;-   —NR⁴C(O)(CH₂)_(m)CH₃-   —NR⁴C(O)(CH₂)_(o)NR⁴R⁵;-   —O(CH₂)_(o)R⁷;-   or —OC(O)R⁴;    wherein-   m is 0, 1, 2 or 3;-   o is 1, 2 or 3;-   R⁴ and R⁵ are each independently hydrogen or (C1-C6)alkyl;-   R⁶ is hydrogen, (C1-C6)alkyl or —NR₄R₅;-   R⁷ is hydroxy, cyano, pyrrolidine or NR⁴R⁵;-   R⁸ is morpholine, hydroxy, pyrrolidine, tetrahydropyran,    (C1-C6)alkyl or NR⁴R⁵;-   R⁹ is morpholine, pyrrolidine, tetrahydropyran, or (C1-C6)alkyl;    and the pharmaceutically acceptable salts thereof.

The disclosed invention also relates to compounds of the formula:

wherein n is 1-4;

R₁ may be one or more optional substituents selected from the groupconsisting of: (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,(C1-C6)alkoxy, (C2-C6)alkenyloxy, (C2-C6)alkynyloxy, (C1-C6)alkylthio,(C1-C6)alkylsulphinyl, (C1-C6)alkylsulphonyl, (C1-C6)alkylamino,di-[(C1-C6)alkyl]amino, (C1-C6)alkoxycarbonyl, N-(C1-C6)alkylcarbamoyl,N,N-di-[(C1-C6)alkyl]carbamoyl, (C2-C6)alkanoyl, (C2-C6)alkanoyloxy,(C2-C6)alkanoylamino, N-(C1-C6)alkyl-(C2-C6)alkanoylamino,(C3-C6)alkenoylamino, N-(C1-C6)alkyl-(C3-C6)alkenoylamino,(C3-C6)alkynoylamino, N-(C1-C6)alkyl-(C3-C6)alkynoylamino,N-(C1-C6)alkylsulphamoyl, N,N-di-[(C₁-C6)alkyl]sulphamoyl,(C1-C6)alkanesulphonylamino, N-(C1-C6)alkyl-(C1-C6)alkanesulphonylamino,carboxamide, ethylene, thiophenyl, aminophenyl, trifluoromethyl, halo,trifluoromethoxy, hydroxymethyl, N-pyrrolidino, N-morpholino,phenylthio, (C1-C4)dialkylaminomethyl, methoxyphenyl, amino, hydroxy,carboxyl, phenyl, arylalkyl;

R₂ is selected from the group comprising oxazole;benzo[2,1,3]thiadiazole; quinoxaline; 1H-imidazo[4,5-c]pyridine;imidazo[1,2-a]pyridine; indole; pyrazine; dihydrobenzofuran; furan;thiophene; isoquinoline; benzofuran; benzothiazole;3,4-dihydro-2H-benzo[b][1,4]dioxepine; 1H-imidazo[4,5-b]pyridine;pyrazolo[1,5-a]pyrimidine; oxazolo[4,5-b]pyridine; 1H-benzoimidazole;[1,8]naphthyridine; or [1,5]naphthyridine;

R₃ may be one or more optional substituents selected from the groupconsisting of (C1-C6 alkyl);

and the pharmaceutically acceptable salts thereof.

Preferred embodiments also include compounds wherein R² may be asfollows. The numbers preceding the specified heterocycle indicate thepoint of attachment of the specified heterocycle:

a) substituted or unsubstituted 2, 5, 6 or 7-quinoxaline;

b) substituted or unsubstituted 7-quinoxaline-2-one;

c) substituted or unsubstituted 6 or 7-isoquinoline;

d) substituted or unsubstituted 5 or 6-benzothiazole;

e) substituted or unsubstituted 4 or 5-indole;

f) substituted or unsubstituted 5-(3,4)dihydrobenzofuran;

g) substituted or unsubstituted 2, 3, 5 or 7-benzofuran;

h) substituted or unsubstituted 3, 5 or 6-pyrazolo[1,5-a]pyrimidine;

i) substituted or unsubstituted 2 or 3-[1,5]naphthyridine;

j) substituted or unsubstituted 4 or 8-[1,6]naphthyridine;

k) substituted or unsubstituted 5-oxazole;

l) substituted or unsubstituted 4 or 5-benzo[1,2,5]thiadiazole;

m) substituted or unsubstituted 2-pyrazine;

n) substituted or unsubstituted 7-pyrido[2,3-b]pyrazine;

o) substituted or unsubstituted 3-thiophene;

p) substituted or unsubstitued 3-furan;

q) substituted or unsubstituted 2-1H-imidazo[4,5-b]pyridine;

r) substituted or unsubstituted 6-imidazo[1,2-a]pyridine;

s) substituted or unsubstituted 5,6-1H-benzoimidazole;

t) substituted or unsubstituted 2-oxazolo[4,5-b]pyridine; or

u) substituted or unsubstituted 7-3,4-dihydro-2H-benzo[b][1,4]dioxepine.

Some preferred substituents include (C1-C4) alkyl; (C1-C4 alkoxy);halogen; —O(CH₂)_(m)NR⁴R⁵; —C(O)NR⁴R⁵; —O(CH₂)_(m)OH; NR⁴R₅;—OC(O)(C1-C4)alkyl; —C(O)OR⁴; or —C(O)NH(CH₂)_(m)NR⁴R⁵.

More preferred embodiments of the invention include the following:

-   -   Compounds according to the formula:

wherein:

-   R₁ is hydrogen or methyl;-   R_(A) is hydrogen; —CH₂ N-morpholino; —CH₂C(O)N-morpolino;    —C(O)OCH₂CH₃; —C(O)NH(CH₂)₂N(CH₃)₂; —NHCH(CH₂)₂CH₂CH(CH₂)₂CH₃;    —NHC(O)CH₃; —C(O)NH₂; or 4-chlorophenyl;    and the pharmaceutically acceptable salts thereof.

Other preferred embodiments of the invention include the following:

-   -   Compounds of the formula:

wherein:

-   R₁ is hydrogen or methyl;-   R_(b) is hydrogen; methyl; or —(CH₂)₃O-tetrahydropyran; and the    pharmaceutically acceptable salts thereof.

Also compounds according to the formula:

wherein:

R₁ is hydrogen or methyl; & is hydrogen; -methyl; —(CH₂)₃OH;—(CH₂)₃N(CH₃)₂;

-   —(CH₂)₃N(CH₂CH₃)₂; or —(CH₂)X, wherein X is either N-morpholine,    N-pyrrolidine or N-piperidine; and the pharmaceutically acceptable    salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term “effective amount” as used in “an effective amount of acompound of Formula I,” for example, refers to an amount of a compoundof the present invention that is capable of inhibiting TGF beta.

The general chemical terms used herein have their usual meanings. Forexample, as used herein, the term “C₁-C₄ alkyl”, alone or incombination, denotes a straight-chain or branched-chain C₁-C₄ alkylgroup consisting of carbon and hydrogen atoms, examples of which aremethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and thelike.

The term “C₁-C₄ alkoxy”, alone or in combination, denotes an alkyl groupas defined earlier, which is attached via an oxygen atom, such as, forexample, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, andthe like. The term “C₁-C₄ alkylthio”, alone or in combination, denotesan alkyl group as defined earlier and is attached via a sulfur atom, andincludes methylthio, ethylthio, isobutylthio, and the like.

As used herein, the term “halo” or “halogen” represents fluorine,chlorine, bromine, or iodine. The term “hydroxy,” alone or incombination, represents an —H moiety. The term “carboxy” or “carboxyl”refers to a carboxylic acid. The term “carboxamide” refers to a carbonylsubstituted with an —NH₂ moiety. The term “oxo” refers to a carbonylgroup.

As used herein, the term “aryl” represents a substituted orunsubstituted phenyl or naphthyl. Aryl may be optionally substitutedwith one or more groups independently selected from hydroxy, carboxy,C₁-C₆ alkoxy, C₁-C₆ alkyl, halogen, carboxamide, trifluoromethyl,hydroxymethyl, and hydroxy(C₁-C₄)alkyl.

As used herein, the term “C₁-C₆ alkyl” refers to straight or branched,monovalent, saturated aliphatic chains of 1 to 6 carbon atoms andincludes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term “C₁-C₆alkyl” includes within its definition the terms “C₁-C₄ alkyl” and “C₁-C₃alkyl.”

As used herein, the term “C₁-C₉ alkyl” refers to straight or branched,monovalent, saturated aliphatic chains of 1 to 9 carbon atoms andincludes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl, etc.

“C₁-C₆ alkenyl” refers to a straight or branched, divalent, unsaturatedaliphatic chain of 1 to 6 carbon atoms and includes, but is not limitedto, methylenyl, ethylenyl, propylenyl, isopropylenyl, butylenyl,isobutylenyl, t-butylenyl, pentylenyl, isopentylenyl, hexylenyl.

“C₁-C₆ alkoxycarbonyl” represents a straight or branched C₁-C₆ alkoxychain, as defined above, that is attached via the oxygen atom to acarbonyl moiety. Typical C₁-C₆ alkoxycarbonyl groups includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, t-butoxycarbonyl and the like.

The term “di[(C1-C6 alkyl)]amino” refers to a group of the formula:

wherein each R group independently represents a “C₁-C₆ alkyl” group, asdefined above.

As used herein, the term “heteroaryl” means an aryl moiety, whichcontains 1-5 heteroatoms selected from O, S, and N. Examples ofheteroaryl groups include pyrrolyl, pyrazolyl, pyranyl, thiopyranyl,furanyl, imidazolyl, pyridyl, thiazolyl, triazinyl, phthalimidyl,indolyl, purinyl, and benzothiazolyl.

“Arylalkyl” refers to aryl groups attached to alkyl groups, preferablyhaving 1 to 6 carbon atoms in the alkyl moiety and 6 to 10 carbon atomsin the aryl moiety. Such arylalkyl groups are exemplified by benzyl,phenethyl, and the like.

Unless otherwise constrained by the definition for arylalkyl, sucharylalkyl groups can be optionally substituted with 1 to 5 substituents,more preferably 1 to 3 substituents, selected from the group consistingof halo, hydroxy, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ alkoxy, di(C₁-C₆alkyl)amino, trifluoromethyl, trifluoromethoxy, carbamoyl, pyrrolidinyl,—S(O)_(m)—(C₁-C₆ alkyl), and —S(O)_(m)-(phenyl), wherein m can be 0, 1,or 2. The arylalkyl groups may be optionally substituted on the aryl,moiety, the alkyl moiety, or both the aryl moiety and the alkyl moiety.

Abbreviations used herein include the following:

-   -   The term Pd₂(dba)₃ refers to        tris(dibenzylideneacetone)dipalladium.    -   The term dppf refers to 1,1′-bis(diphenylphosphino) ferrocene.    -   The term DMAP=4-(N,N-dimethylamino)pyridine.    -   The term DMF refers to N,N-dimethylformamide.    -   The term DMSO refers to dimethylsulfoxide.    -   The term eq refers to equivalent.    -   The term ES refers to electron spray.    -   The term h refers to hour(s).    -   The term HPLC refers to high performance liquid chromatography.    -   The term L refers to liter.    -   The term min refers to minutes.    -   The term mL refers to milliliter.    -   The term mmol refers to millimole.    -   The term Mp refers to melting point.    -   The term MPLC refers to medium pressure liquid chromatography.    -   The term MS refers to mass spectrum.    -   The term THF refers to tetrahydrofaran.    -   The term THP refers to tetrahydropyran.    -   The term TLC refers to thin layer chromatography.    -   The term W refers to watts.

Compounds Exemplified in the Application Include the Following

It will be understood that the number preceding the compound namecorresponds to the example wherein the compound is exemplified.

-   -   a)        2-(Pyridin-2-yl)-3-(thiophen-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Example 1)    -   b)        5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole        (Ex. 2)    -   c)        3-(2-Phenyl-oxazol-5-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 3)    -   d) 4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo        [1,2-b]pyrazol-3-yl]-benzo[2,1,3]thiadiazole (Ex. 4)    -   e)        5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]benzo[2,1,3]thiadiazole        (Ex. 5)    -   f)        6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline        (Ex. 6)    -   g)        5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline        (Ex. 7)    -   h) 2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo        [1,2-b]pyrazol-3-yl]-1H-imidazo[4,5-b]pyridine (Ex. 8)    -   i)        2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-imidazo[4,5-c]pyridine        (Ex. 9)    -   j)        2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole        (Ex. 10)    -   k)        2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-oxazolo[4,5-b]pyridine        (Ex. 11)    -   l)        2-Dimethylamino-N-[6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,8]naphthyridin-2-yl]-acetamide        (Ex. 12)    -   m)        4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,8]naphthyridine        (Ex. 13)    -   n)        2-(Pyridin-2-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 14)    -   o)        7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline        (Ex. 15)    -   p)        4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline        (Ex. 16)    -   q)        3-(4-Fluoro-benzofuran-7-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 17)    -   r)        2-Methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole        (Ex. 18)    -   s)        2-Methyl-5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole        (Ex. 19)    -   t)        3-(4-Fluoro-benzofuran-7-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 20)    -   u)        7-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline        (Ex. 21)    -   v)        1-Methyl-5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole        (Ex. 22)    -   w)        1-Methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H        indole (Ex. 23)    -   x)        3-(Pyrazin-2-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 24)    -   y)        2-(6-Methyl-pyridin-2-yl)-3-(pyrazin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 25)    -   z)        3-(2,3-Dihydro-benzofuran-5-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 26)    -   aa)        3-(Furan-3-yl-2)-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 27)    -   bb)        3-(Furan-3-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 28)    -   cc)        2-(6-Methyl-pyridin-2-yl)-3-(thiophen-3-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 29)    -   dd)        3-(Benzofuran-5-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 30)    -   ee)        6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine        (Ex. 31)    -   ff)        3-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 32)    -   gg)        3-Morpholin-4-ylmethyl-6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine        (Ex. 33)    -   hh)        1-Morpholin-4-yl-2-[6-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-ethanone        (Ex. 34)    -   ii)        6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic        acid (Ex. 35)    -   jj)        6-[2-(Pyridin-2-yl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-imidazo[1,2-a]pyridine        (Ex. 36)    -   kk)        1-Morpholin-4-yl-2-[6-(2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-imidazo[1,2-a]pyridin-2-yl]-ethanone        (Ex. 37)    -   ll)        6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic        acid (2-dimethylamino-ethyl)-amide (Ex. 38)    -   mm)        6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylic        acid ethyl ester (Ex. 39)    -   nn)        6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylic        acid amide (Ex. 40)    -   oo)        8-Fluoro-6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine        (Ex. 41)    -   pp)        [6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine        (Ex. 42)    -   qq)        N-[6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridin-3-yl]-acetamide        (Ex. 43)    -   rr)        6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic        Acid Amide (Ex. 44)    -   ss)        6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylic        Acid (2-Dimethylamino-ethyl)-amide (Ex. 45)    -   tt)        6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic        Acid Amide (Ex. 46)    -   uu)        7-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine        (Ex. 47)    -   vv)        3-(4-Chloro-phenyl)-6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b)pyrazol-3-yl]-imidazo[1,2-a]pyridine        (Ex. 48)    -   ww)        5-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole        (Ex. 49)    -   xx)        1-Methyl-6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole        (Ex. 50)    -   yy)        1-Methyl-6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole        (Ex. 51)    -   zz)        1-Methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole        (Ex. 52)    -   aaa)        1-Methyl-5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole        (Ex. 53)    -   bbb)        5-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole        (Ex. 54)    -   ccc)        6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole        (Ex. 54)    -   ddd)        5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole        (Ex. 55)    -   eee)        6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole        (Ex. 55)    -   fff)        2-{7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrido[2,3-b]pyrazin-2-yloxy}-ethanol        (Ex. 55a)    -   ggg)        7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-quinoxalin-2-one        (Ex. 55b)    -   hhh)        3-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl][1,5]naphthyridine        (Ex. 55c)    -   iii) 3-[6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo        [1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propan-1-ol (Ex. 56)    -   jjj)        3-[6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propan-1-ol        (Ex. 57)    -   kkk) Methanesulfonic Acid        3-[6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propyl        Ester (Ex. 57a)    -   lll) Methanesulfonic acid        3-[6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propyl        ester (Ex. 57b)    -   mmm)        Dimethyl-[3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazol-1-yl]propyl]amine        (Ex. 58)    -   nnn)        Diethyl-[3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazol-1-yl]propyl]amine        (Ex. 59)    -   ooo)        6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-(3-morpholin-4-yl-propyl)-1H-benzoimidazole        (Ex. 60)    -   ppp)        6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-(3-pyrrolidin-1-yl-propyl)-1H-benzoimidazole        (Ex. 61)    -   qqq)        6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-(3-piperidin-1-yl-propyl)-1H-benzoimidazole        (Ex. 62)    -   rrr)        5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-H-benzoimidazole        (Ex. 63)    -   sss)        6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline        (Ex. 64)    -   ttt)        2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline        (Ex. 65)    -   uuu)        2-[7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalin-2-yloxy]-ethanol        (Ex. 66)    -   vvv)        4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,6]naphthyridine        (Ex. 66a)    -   www)        6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline        (Ex. 67)    -   xxx)        6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole        (Ex. 68)    -   yyy)        2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole        (Ex. 69)    -   zzz)        5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazol-2-ylamine        (Ex. 70)    -   aaaa)        4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole        (Ex. 71)    -   bbbb)        3-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole        (Ex. 72)    -   cccc)        3-(2,3-Dihydro-benzofuran-5-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 73)    -   dddd) Acetic acid        5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzofuran-3-yl        ester (Ex. 74)    -   eeee)        3-(5-Methoxy-benzofuran-3-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 75)    -   ffff)        5-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzofuran-2-carboxylic        acid (Ex. 76)    -   gggg)        3-(Benzofuran-2-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole        (Ex. 77)    -   hhhh)        5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine        (Ex. 78)    -   iiii)        5-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine        (Ex. 79)    -   jjjj)        5-[2-(Pyridin-2-yl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-pyrazolo[1,5-a]pyrimidine        (Ex. 80)    -   kkkk)        8-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-[1,6]naphthyridine        (Ex. 80a)    -   llll)        3-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-pyrazolo[1,5-a]pyrimidine        (Ex. 81)    -   mmmm)        2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,5]naphthyridine        (Ex. 82)    -   nnnn)        2-Chloro-7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline        (Ex. 83)    -   oooo)        Dimethyl-(2-{7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalin-2-yloxy}-ethyl)-amine        (Ex. 84)    -   pppp)        Dimethyl-(2-{7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalin-2-yloxy}-propyl)-amine        (Ex. 85)    -   qqqq)        7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline-2-carboxylic        acid amide (Ex. 86)

The compounds exemplied above are merely representative of the inventionand are not limiting in any fashion.

The compounds disclosed herein can be made according to the followingschemes and examples. The examples should in no way be understood to belimiting in any way as to how the compounds may be made.

The skilled artisan will appreciate that the introduction of certainsubstituents will create asymmetry in the compounds of Formula (I),(Ia), (II), (III), (IV) and (V). The present invention contemplates allenantiomers and mixtures of enantiomers, including racemates. It ispreferred that the compounds of the invention containing chiral centersare single enantiomers.

The compounds of the present invention can be prepared by a variety ofprocedures, some of which are illustrated in the Schemes below. It willbe recognized by one of skill in the art that the individual Steps inthe following schemes may be varied to provide the compounds of Formula(Ia). The particular order of Steps required to produce the compounds ofFormula (Ia) is dependent upon the particular compound beingsynthesized, the starting compound, and the relative lability of thesubstituted moieties.

Scheme I, step a, depicts an acylation of an appropriate aromatic and/orheteroaromatic compound of formula (1) and an appropriate carbonylcompound of formula (2) to give a compound of formula (5). The aromaticand/or heteroaromatic compounds of formula (1) are commerciallyavailable or can be produced by methods known in the art (Chem. Pharm.Bull. 1971, 1857). Compounds of formula (2) are commercially availableor can be made as taught in PCT/US002/11884. The acylation of formula(1) requires that X, of formula (2), be a suitable leaving group, suchas C1-C6 alkoxy, halo, C1-C6 thioether, or preferably disubstitutedamino. The reaction is typically carried out in the presence of asuitable base, such as lithium diisopropylamide, potassiumbis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, sodiumbis(trimethylsilyl)amide, sodium hydride, lithium hydride, potassiumhydride, sodium alkoxides (sodium methoxide, or sodium ethoxide) orpotassium alkoxides (potassium methoxide, or potassium ethoxide), orpreferably potassium bis(trimethylsilyl)amide. Generally, the reactionis carried out in suitable solvents, such as tetrahydrofuran, toluene,or a combination of such, at temperatures of about −78° C. to ambienttemperature. The product, formula (5), can be isolated and purified bytechniques well known in the art, such as precipitation, filtration,extraction, evaporation, trituration, chromatography, andrecrystallization. Another variation of the acylation, step a, is to usea nitrile compound of formula (3) in place of the aromatic- orheteroaromatic-methyl compounds of formula (1). The product, formula(4), can be transformed to formula (5) by hydrolysis of the nitrilegroup and then subsequent decarboxylation. Generally, a compound offormula (4) is dissolved in a hydrogen halide acid solution, preferablyhydrogen chloride. The reaction is carried out at temperatures of aboutambient to refluxing for 1 to 48 hours. This type of reaction is wellknown and appreciated in the art (Larock, R. C., Comprehensive OrganicTransformations, copyright 1989, VCH, pp 993). Compounds of formula (3)can be acquired by treatment of an appropriately substituted aromatic-or heteroaromatic-methyl group with a halogenating reagent, such asN-halosuccinimides, preferably N-bromosuccinimide in a suitable solvent,preferably carbon tetrachloride and subsequently reacting thearomatic-halomethylene intermediate with a nitrile source, such aslithium cyanide, potassium cyanide, trimethylsilyl cyanide, orpreferably sodium cyanide. The reaction is carried out in a suitablesolvent such as water, tetrahydrofuran, N-methylpyrrolidin-2-one,dimethylsulfoxide or preferably N,N-dimethylformamide. The reaction iscarried out at 0° C. to refluxing for 1 to 48 hours, as shown in step b,to afford the nitrile compounds of formula (3), (Larock, R. C.,Comprehensive Organic Transformations, copyright 1989, VCH, pp 313; Eur.J. Org. Chem. 1999, 2315-2321).

In Scheme I, step d, compound of formula (5) is contacted to anappropriate compound of formula (6), this type of compound is known andappreciated in the art (Taylor, Edward C.; Haley, Neil F.; Clemens,Robert J., J. Amer. Chem. Soc., 1981, 7743-7752), to give the compoundof formula (7). Typically, the reaction is carried out in an appropriatesolvent, such as acetic acid, ethanol, triethylamine, or preferablypyridine. The reaction is carried out at temperatures of about 60° C. toambient for 4-24 hours. The products can be isolated and purified bytechniques described above.

Scheme II, step e, depicts a ketone of formula (5) affording a hydrazonecompound of formula (8). Typically the reaction is carried out with asuitable source of hydrazine, preferably hydrazine hydrate in an acidicsolution consisting of an alcohol, such as methanol, ethanol, orpropanol, and a hydrogen halo acid catalyst, preferably hydrogenchloride. The product can be isolated and purified by techniquesdescribed above. Compounds of formula (9) are commercially available.Step a previously described, transform the hydrazones of formula (8) tothe hydrazides of formula (11), by acylation with compounds formula (9).The compound of formula (9) can be an appropriate carboxylic acidderivative, where X can be a leaving group previously described,preferably a halogen, most preferably a chloride, and where the sum of pand q can equal 2 or 5 carbons. The reaction is carried out in thepresence of an acid scavenger such as pyridine or triethylamine. Thereagents are combined, and products isolated and purified by techniquesdescribed above. The conversion of amines to amides by acylation is wellknown and appreciated in the art (Larock, R. C., Comprehensive OrganicTransformations, copyright 1989, VCH, pp 979).

Scheme II, step g depicts ring opening of substituted lactones offormula (10) to afford hydrazones of formula (11). Typically, a compoundof formula (8) is contacted with a suitable Lewis acid, preferablytrimethyl aluminum followed by addition of a compound of formula (10)which can give the corresponding alcohol derivatives to be furthertransformed to give compound of formula (11).

In Scheme III, step h depicts the cyclization of a compound of formula(II), where the R group(s) can be any group(s), previously defined asR₁, R₂ or R₃ of Formula (Ia). Typically, the appropriate compound offormula (11) is contacted to a suitable base such as lithiumdiisopropylamide, potassium bis(trimethylsilyl)amide, lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, cesiumcarbonate, lithium hydride, potassium hydride, sodium alkoxides (sodiumhydoxide, sodium methoxide, or sodium ethoxide) or potassium alkoxides(potassium hydroxide, potassium methoxide, or potassium ethoxide), orpreferably sodium hydride. The reaction is carried out in a suitablesolvent, such as tetrahydrofuran, N,N-dimethylformamide,N-methylpyrrolidin-2-one, dimethylsulfoxide, toluene, or preferablytetrahydrofaran, at temperatures of about 0 to 100° C. Step i depictsthe cyclization of a compound of formula (7). Typically, the appropriatecompound of formula (7) is contacted to a suitable base such as lithiumdiisopropylamide, potassium bis(trimethylsilyl)amide, lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodiumhydride, lithium hydride, potassium hydride, sodium alkoxides (sodiumhydoxide, sodium methoxide, or sodium ethoxide) or potassium alkoxides(potassium hydroxide, potassium methoxide, or potassium ethoxide), orpreferably cesium carbonate. The reaction is carried out in a suitablesolvent, such as tetrahydrofuran, N,N-dimethylformamide,dimethylsulfoxide, toluene, or preferably N-methylpyrrolidin-2-one, attemperatures of about 0 to 100° C. The products can be isolated andpurified by techniques well known in the art, such as precipitation,filtration, extraction, evaporation, trituration, chromatography, andrecrystallization.

Another variation a skilled artisan would appreciate is Method B for theformation of Formula (I), in Scheme III, step j, which is known andappreciated in the art (Ranganathan, Darshan; Bamezai, Shakti,Tetrahedron Lett., 1983, 1067-1070). For example, an alkyne (12) isreacted with a compound (13) in a suitable solvent, such astetrahydrofuran, N,N-dimethylformamide, or toluene, preferably xylene attemperatures of about 0 to 150° C. The products can be isolated andpurified by techniques described above.

Another useful intermediate in the synthesis of compounds of Formula Iis shown in Scheme IV. Scheme IV, step k, depicts a Claisen condensationof two appropriately substituted carbonyl esters, where X for bothcompounds of formula (2) and formula (14) is a suitable leaving group aspreviously described, preferably a C1-C6 alkoxy group. The Claisencondensation is well known and appreciated in the art (March, J.,Advanced Organic Chemistry, copyright 1985, John Wiley and Sons, Inc.,pp 437-439). The products of formula (15) can be isolated and purifiedby techniques described above.

In Scheme IV, step d, conditions can be applied to a compound of formula(I 5) with the appropriate compound of formula (6), to give a compoundof formula (16). Typically, the reaction is carried out in a suitablesolvent such as ethanol, N-methylpyrrolidin-2-one, or preferablypyridine. The reaction is carried out at temperatures of about 60° C. toambient for 4-24 hours. The products can be isolated and purified bytechniques described above.

Step a, as described above, depicts the cyclization of a compound offormula (16) to give an optionally substituted compound of formula (17).Typically, the appropriate compound of formula (16) is reacted with asuitable base, preferably cesium carbonate, in a suitable solvent,preferably N,N-dimethylformamide, at temperatures of about 0 to 100° C.Optionally, a hydrolysis of the carboxyl ester of formula (117) can beperformed. The products can be isolated and purified by techniquesdescribed above.

Step l depicts the transformation of a carboxylic acid, formula (17), toa halide of formula (118). This transformation is well known andappreciated in the art (Larock, R. C., Comprehensive OrganicTransformations, 2^(nd Ed., copyright) 1999, John Wiley & Sons, pp741-742).

Step m depicts the transformation of a heteroaryl halide, formula (118),to a heteroaryl boronic acid or ester formula (19). This transformationis well known and appreciated in the art (Li, Wenjie; Nelson, Dorian P.et al, J. Org. Chem, 2002, 5394-5397).

Scheme V depicts an alternative approach to the synthesis of thecompound of formula (18). One skilled in the art would appreciate theconversion of various acetylpyridines of formula (20) to hydrazones offormula (21) through step n. This conversion is known in the art (Org.Synth. 1988, VI, pg. 12, J. Org. Chem. 1997, 62, 287-291). Scheme V,step o depicts the acylation of a hydrazone compound of formula (21)with a compound of formula (22) to give the product of formula (23).Typically the compound of formula (21) is contacted with a suitablebase, such as potassium bis(trimethylsilyl)amide, lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodiumhydride, lithium hydride, potassium hydride, sodium alkoxides (sodiummethoxide, or sodium ethoxide) or potassium alkoxides (potassiummethoxide, or potassium ethoxide), or preferably lithiumdiisopropylamine. Generally, the reaction is carried out in suitablesolvents, such as tetrahydrofuran, toluene, or a combination of such, attemperatures of about −78° C. to ambient temperature. The product,formula (23), can be isolated and purified by techniques well known inthe art, such as precipitation, filtration, extraction, evaporation,trituration, chromatography, and recrystallization, or can be carriedforward in scheme (IV) without purification. Scheme (IV), step p,depicts the conversion of a β-ketohydrazone of formula (23) to asubstituted pyrazole of formula (24). Typically, a compound of formula(23) is treated with a source of hydrazine such as hydrazine, hydrazinemonohydrate, hydrazine hydrate, or preferably hydrazine hydrochloride inan appropriate solvent such as tetrahydrofuran, ethanol, methanol,water, or preferably a combination of these at temperatures of aboutambient temperature to reflux. The product, formula (24), can beisolated and purified by techniques well known in the art, such asprecipitation, filtration, extraction, evaporation, trituration,chromatography, and recrystallization. Step q depicts the cyclization ofa haloalkylpyrazole compound of formula (24) to a5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole of formula (25). Typically, theappropriate compound of formula (24) is reacted with a suitable base,preferably sodium hydride, in a suitable solvent, preferablyN,N-dimethylformamide, at temperatures of about 0 to 100° C. Theproducts of formula (25) can be isolated by methods described above.Step r depicts the halogenation of a compound of formula (25) to give acompound of formula (18). Typically the appropriate compound of formula(25) is contacted with a halogenating agent such as N-chlorosuccinamide,N-iodosuccinamide, chlorine, bromine, iodine, or preferablyN-bromosuccinamide in an appropriate solvent such as dichoromethane,chloroform, benzene, or preferably N,N-dimethylformamide at temperaturesof about 0 to 50° C.

Scheme VI, step s depicts the addition and cyclization of a compound offormula (26) to a compound of formula (17) to give additional compoundsof the invention (Formula I). The R group(s) can be any group(s),previously defined as R₁, R₂, or R₃ of Formula II and the X, Y, and Z offormula (26) can be nitrogen, nitrogen or oxygen, and carbon or oxygenrespectively. Typically, a compound capable of producing the acid halideof a compound of formula (17) such as phosphorous pentachloride,phosphorous oxybromide, or preferably phosphorous oxychloride is addedto a mixture of a compound of formula (17) and a compound of formula(26). The reaction is heated at temperatures from 30 to about 120° C.for 1 to 18 hours. The products of Formula II can be purified by methodsdescribed above.

Scheme VII, step j, depicts the palladium-catalyzed coupling of acompound of formula (17) with a compound of formula (19) to give acompound of the invention (Formula Ia). Typically, the halide of formula(17) is used as a leaving group in combination with a compound offormula (19) in the presence of a suitable catalyst, preferablytetrakis(triphenylphosphine)palladium(0), and a suitable base, such aspotassium carbonate, to further give compounds of Formula (I) (Suzukireaction see: Miryaura, N.; Yanagi, T.; Suzuki, A. ThePalladium-Catalyzed Cross Coupling Reaction of Phenylboronic Acid withHaloarenes in the Presence of Bases. Synth. Commun. 1981, 513-518). Thecompounds of formula (19) are commercially available or can be producedby methods known in the art (Li, Wenjie; Nelson, Dorian P. et al, J.Org. Chem. 2002, 5394-5397). In the same way, a compound of formula (18)can be used in combination with a compound of formula (20), where Y canbe an appropriate leaving group such as a halide, in the presence of asuitable palladium catalyst, preferablytetrakis(triphenylphosphine)palladium(0), and a suitable base, such aspotassium carbonate, to further give compounds of Formula (I) (Suzukireaction see: Miryaura, N.; Yanagi, T.; Suzuki, A. ThePalladium-Catalyzed Cross Coupling Reaction of Phenylboronic Acid withHaloarenes in the Presence of Bases. Synth. Commun. 1981, 513-518).

The skilled artisan will also appreciate that not all of thesubstituents in the compounds of Formula (Ia) will tolerate certainreaction conditions employed to synthesize the compounds. These moietiesmay be introduced at a convenient point in the synthesis, or may beprotected and then deprotected as necessary or desired. Furthermore, theskilled artisan will appreciate that in many circumstances, the order inwhich moieties are introduced is not critical.

The skilled artisan will appreciate that the compounds of Formula (Ia)may be formed into acid addition salts using pharmaceutically acceptableacids. The formation of acid-addition salts is well known andappreciated in the art.

The following preparations and examples further illustrate thepreparation of compounds of the present invention and should not beinterpreted in any way as to limit the scope. Those skilled in the artwill recognize that various modifications may be made while notdeparting from the spirit and scope of the invention. All publicationsmentioned in the specification are indicative of the level of thoseskilled in the art to which this invention pertains.

Preparation 1 Preparation of3-Bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo [1,2-b]pyrazole

A. Preparation of 3-(6-Methyl-pyridin-2-yl)-3-oxo-propionic Acid EthylEster

Stir a mixture of sodium ethoxide (90 g, 1.32 mol, 2 eq), toluene (0.5L, 5 vol), and ethyl acetate (0.2 L, 1.98 mol, 3 eq) in a 2 L flaskequipped with reflux condenser, mechanical stirrer, and nitrogen inlet.After 1 h, add 6-methyl-pyridine-2-carboxylic acid methyl ester (Cheung,Y, Tetrahedron Lett. 1979, 40, 3809-10; 100 g, 0.66 mol). Heat themixture at reflux (92° C.) for 20 h. Cool the mixture to roomtemperature and acidify with glacial acetic acid to pH 6. Wash theresulting gel with water (0.5 L). Separate the layers and extract theaqueous layer with toluene (1×0.5 L) Dry the combined organic layers(sodium sulfate), filter, and concentrate in vacuo to yield thesubtitled product (154 g) as a dark oil in 86% purity by HPLC analysis.MS ES⁺ m/e 208 (M+1).

B. Preparation of3-(6-Methyl-pyridin-2-yl)-3-(2-oxo-pyrrolidin-1-ylimino)-propionic AcidEthyl Ester

Add 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem. 1969,9(2), 58; 99.4 g, 0.73 mol) to a 3 L flask equipped with mechanicalstirrer and nitrogen inlet. Add3-(6-methyl-pyridin-2-yl)-3-oxo-propionic acid ethyl ester (Preparation1, Part A; 154 g, 0.66 mol), then pyridine (280 mL). Stir the reactionmixture at room temperature for 20 h. Dilute the mixture with water (200mL) and extract with toluene (2×250 mL). Combine the organic layers,filter, and concentrate in vacuo to yield the subtitled product (201 g)as a dark oil. MS ES⁺ m/e 290 (M+1).

C. Preparation of2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylicacid

Add sodium ethoxide (90 g, 1.32 mol), toluene (5 L) and3-(6-methyl-pyridin-2-yl)-3-(2-oxo-pyrrolidin-1-ylimino)-propionic acidethyl ester (Preparation 1, Part B; 201 g, 0.661 mol) to a 22 L flaskequipped with a mechanical stirrer, nitrogen inlet and a refluxcondenser. Heat the mixture at 100° C. for 24 h then cool to roomtemperature. Add water (4 L) and adjust the pH to 4 with concentratedhydrochloric acid. Separate the organic layer and extract the aqueousportion with 10% isopropyl alcohol in chloroform is (3×4.5 L). Combinethe organic layers, dry (sodium sulfate), filter, and concentrate invacuo to yield the subtitled product (138 g, 86% yield) as a yellowsolid in 78% purity by HPLC analysis. MS ES⁺ m/e 244 (M+1).

D. Preparation of3-Bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2b]pyrazole

Treat a solution of2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylicacid (1.4 g, 5.8 mmol) in N,N-dimethylformamide (20 mL) withN-bromosuccinamide (1 g, 5.6 mmol) and stir at room temperature for 16h. Dilute the mixture with ethyl acetate and wash three times withwater, once with brine, dry (sodium sulfate), filter, and concentrate invacuo to yield the title compound (1.5 g, 94%) as light yellow solid. MSES⁺ m/e 278 (M+1).

Preparation 2 Preparation of2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid

Place tetrahydrofuran (28.0 mL) in a 100 mL round-bottom flask equippedwith a temperature probe, a magnetic stirrer, and a septum and put undera nitrogen atmosphere. Add3-bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation 1, 1.44 g, 5.18 mmol) and triisopropyl borate (3.10 mL,13.5 mmol). Cool the mixture to −78° C. using a dry ice/acetone bath.Add 1.4M n-butyllithium in hexanes (8.80 mL, 12.4 mmol) dropwise via asyringe pump over 10 min keeping the temperature below −40° C. Removethe dry ice/acetone bath and allow the reaction mixture to warm to roomtemperature. Add saturated aqueous ammonium chloride (10 mL) and extractwith chloroform (2×1 00 mL). Combine the organic layers, dry over solidsodium chloride, and remove the solvent under reduced pressure to affordan oil. Purify the oil by normal phase flash chromatography (120 gBiotage KP-Sil 40 L: 100% ethyl acetate in hexanes for 25 min, 0-10%methanol in ethyl acetate in ramp over 15 min, then 10% methanol inethyl acetate) to yield the title compound (910 mg, 73%). MS ES⁺ m/e 244(M+1).

Preparation 3 Preparation of2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid

A. Preparation of 3-Oxo-3-(pyridin-2-yl)-propionic Acid Ethyl Ester

Stir a mixture of sodium ethoxide (360 g, 5.29 mol, 2 eq), toluene (4L), ethanol (18 mL, 0.265 mol, 0.1 eq) and ethyl acetate (1.04 L, 10.58mol, 4 eq) in a 22 L flask equipped with a reflux condenser, nitrogeninlet and mechanical stirrer. Stir for 1 h as the mixture warms to 26°C. Add pyridine-2-carboxylic acid ethyl ester (Fluka; 400 g, 2.65 mol, 1eq) and heat the mixture to reflux (90° C.) for 18 h. Cool the mixtureto room temperature. Dilute with toluene (8 L), wash with water (6 L),and separate the layers. Acidify the aqueous layer to pH 5 with glacialacetic acid. Extract with ethyl acetate (2×4 L), dry the combinedorganic layers (sodium sulfate), filter and concentrate in vacuo toyield the subtitled compound (466 g, 91% yield) as a dark oil in 93%purity by HPLC analysis. MS ES⁺ m/e 194 (M+1).

B. Preparation of3-(2-Oxo-pyrrolidin-1-ylimino)-3-(pyridin-2-yl)-propionic acid ethylester

Place 1-aminopyrrolidin-2-one hydrochloride (Zubek, A. Z. Chem., 1969,9(2), 58; 155.6 g, 1.14 mol) in a 3 L flask equipped with mechanicalstirrer and nitrogen inlet. Add 3-oxo-3-pyridin-2-yl-propionic acidethyl ester (200 g, 1.04 mol) then pyridine (400 mL). Stir the reactionmixture at room temperature for 20 h. Dilute the mixture with water (500mL), and extract with toluene (2×500 mL). Combine the organic layers,dry (sodium sulfate), filter and concentrate in vacuo to yield thesubtitled compound as a dark oil (280 g, 98%). MS ES⁺ m/e 276 (M+1).

A. Preparation of2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic Acid

Add sodium ethoxide (145 g, 2.03 mol), followed by toluene (7 L) and3-(2-oxo-pyrrolidin-1-ylimino)-3-pyridin-2-yl-propionic acid (280 g,1.02 mol) to a 22 L flask equipped with mechanical stirrer, nitrogeninlet and a reflux condenser. Heat the mixture to 100° C. for 21 h. Coolto room temperature. Add water (6 L) and adjust to pH 5 withconcentrated hydrochloric acid. Separate the organic layer and extractthe aqueous layer with 10% isopropyl alcohol in chloroform (2×9 L).Combine the organic layers, dry (sodium sulfate), filter and concentratein vacuo to yield the title compound as a yellow solid (218 g, 93%). MSES⁺ m/e 230 (M+1).

Preparation 4 Preparation of3-Bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Stir a mixture of2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid(Preparation 3; 2 g, 8.7 mmol), sodium bicarbonate (3.3 g, 38.4 mmol)and N-bromosuccinamide (1.7 g, 9.6 mmol) in DMF (50 mL) at roomtemperature for 2 h. Dilute the crude mixture with 50 mL of water and100 mL of ethyl acetate. Separate the ethyl acetate layer, extract withsaturated brine, dry over anhydrous sodium sulfate, filter, andevaporate to a solid mass. Purify by MPLC (SiO₂, 50% ethylacetate-hexane) to obtain the title compound (1.62 g, 70%) as a creamsolid. MS ES⁺ m/e 264 (M+1), MS ES⁺ m/e 266 (M+2).

Preparation 4a General Procedure for Preparation of2-[5-(alkylchloro)-1H-pyrazol-3-yl]-pyridines

Combine in a flask THF and diisopropylamine (1.3 eq) and cool to −78° C.and add 1.6M n-butyllithium in hexane (1.3 eq). Cool the solution of LDAto −78° C. and add the appropriate N,N-dimethylhydrazone (1 eq)drop-wise as a solution in THF via addition funnel over ˜30 min. Stirthe resulting maroon colored anion for ˜30 min at −78° C. and canulateinto flask containing THF and the appropriate acid chloride (2.5 eq) at−78° C. Remove the cold bath upon completion of addition and allow thereaction to warm to 0-5° C. Add hydrazine mono-hydrochloride (1.9 eq),4:1 ethanol/water and heat at reflux for 2 h. Cool the reaction andconcentrate. Dilute with methylene chloride and water and transfer to aseparatory funnel. Add saturated sodium bicarbonate, shake and separatelayers. Extract the aqueous layer with methylene chloride, wash thecombined organic layer with 1:1 saturated bicarbonate/brine and dry oversodium sulfate. Purify using a silica gel plug in a scintered glassfunnel using silica gel and topped with sand and piece of filter paper.Pre-wet the column with methylene chloride and pour the crude organicsolution containing drying agent on top of the column. Elute with 75%hexane/25% EtOAc, 50% hexane/50% EtOAc, 25% hexane/75% EtOAc andconcentrate to obtain the desired product in sufficient purity for usein the next step.

Preparation 4b General Procedure for Prepartion of3-Bromo-2-aryl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles and3-Bromo-2-aryl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridines

To a 2 L flask add NaH (60% oil dispersion, 1.2 eq). Wash the NaH withhexane three times and add DMF. Cool the mixture to 0° C. in an ice bathand introduce appropriate 2-[5-(alkylchloro)-1H-pyrazol-3-yl]-pyridine(1 eq) as a solution in DMF over 30 min. Remove the ice bath and stirfor approximately 1 h or until cyclization is complete. Introduce sodiumbicarbonate (1.2 eq) and cool to 0° C. Add N-bromosuccinimide (1.1 eq)slowly and stir for ˜15 min. Remove the cold bath, pour into water,extract into methylene chloride, wash the combined organic layer withwater and brine, dry over sodium sulfate, filter, and concentrate.Purify using silica gel plug in a scintered glass funnel using silicagel topped with sand and a piece filter paper. Pre-wet the column with75% hexane/EtOAc and pour the crude organic on top of the column usingmethylene chloride for the transfer. Elute with 75% hexane/25% EtOAc,50% hexane/50% EtOAc, 25% hexane/75% EtOAc, and EtOAc step gradients toobtain the corresponding product.

Preparation 5 Preparation of2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid

Place tetrahydrofuran (60.0 mL) in a 100 mL round-bottom flask equippedwith a temperature probe, a magnetic stirrer, and a septum and put undera nitrogen atmosphere. Add3-bromo-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation 4, 3.00 g, 11.4 mmol) and triisopropyl borate (6.80 mL,29.5 mmol). Cool the mixture to −78° C. using a dry ice/acetone bath.Add 1.41M n-butyllithium in hexanes (19.3 mL, 27.3 mmol) dropwise via asyringe pump over 10 min keeping the temperature below −40° C. Removethe dry ice/acetone bath and allow the reaction mixture to warm to roomtemperature. Add saturated aqueous ammonium chloride (20 mL) and extractwith chloroform (2×150 mL). Combine the organic layers, dry over solidsodium chloride, and remove the solvent under reduced pressure to affordan oil. Purify by normal phase flash chromatography (120 g BiotageKP-Sil 40 L: ethyl acetate for 25 min, 0-10% methanol in ethyl acetatein ramp over 15 min, then 10% methanol in ethyl acetate) to obtain thetitle product (1.43 g, 55%). MS ES⁺ m/e 230 (M+1).

Preparation 5a General Procedure for Preparation of 3-Boronicacid-2-aryl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles and 3-Boronicacid-2-aryl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridines

Cool a solution of the appropriate (1 eq) in THF using a dry ice/diethylether bath. (−74 C.°). Introduce 2.5 M n-butyllithium in hexanes (2 eq)at a rate such that the temperature does not exceed −60° C. and stir for30 min. Add triisopropyl borate (4 eq) slowly and allow to warm to ˜10°C. over 3 h. Dilute with saturated ammonium chloride and stir for 3 h toovernight. Concentrate and extract into methylene chloride. Collectwhite precipitate by filtration from the water layer and organic layerand rinse with water and dry. Concentrate the organic layer andtriturate the residue with diethyl ether and or hexane to give thecorresponding product as a white solid. Combine solids for finalisolation of the title compound(s).

Preparations 6-8 General Preparation of Aryliodides

Add potassium iodide (2.0-5.0 eq) and copper(I) iodide (0.1-0.5 eq) to asolution of the arylbromide in anhydrous DMF (2.0-7.0 mL) in a 10 mLglass tube. Seal the reaction vessel with a septum and place in themicrowave cavity. Use microwave irradiation of 150 W and heat to 130° C.over 30 seconds. Hold the reaction mixture at this temperature for 3-6h. Cool the reaction vessel to room temperature before opening.Partition the reaction mixture between diethyl ether and water. Extractthe water layer twice with ether then wash the combined extracts withsaturated aqueous ammonium chloride, 5% aqueous lithium chloride, 5%aqueous sodium thiosulfate, water, and brine. Dry the ether layer oversodium chloride, decant, and then remove the solvent under reducedpressure using a rotary evaporator to give the title compound.Alternatively, add diethyl ether to the reaction mixture to precipitatethe inorganic salts. Filter and remove the solvent under reducedpressure to give the title compound. Additional purification may becarried out by passage through silica gel or SCX resin.

The following compounds were prepared via the General Preparation ofAryliodides:

PREPA- RATION Product Starting Material Physical Data 6 7-7-bromoisoquinoline MS ES⁺ m/e 256 iodoisoquinoline (Miller, R. B. etal, J. (M + 1) Org. Chem. 1980, 45, 5312-5315) 7 4- 4-bromoisoquinolineMS ES⁺ m/e 256 iodoisoquinoline (Aldrich) (M + 1) 8 4-fluoro-7-7-bromo-4-fluoro- MS ES⁺ m/e 263 iodo- benzofuran (M + 1) benzofuran(PCT Int. Appl. (2000), WO 2000000196 A1)

Preparation 9 Preparation of6-Bromo-3-(morpholin-4-yl)methyl-imidazo[1,2-a]pyridine

Reflux a solution of 6-bromo-imidazo[1,2-a]pyridine-3-carbaldehyde (J.Med. Chem. 1970, 13(6), 1048-51; 0.45 g, 1.99 mmol), morpholine (1.7 g,19.9 mmol), and acetic acid (0.12 mL, 1.99 mmol) in toluene (200 mL) for3 h. Concentrate to dryness and re-dissolve in methanol (100 mL). Addsodium borohydride (0.226 g, 5.99 mmol) in portions and stir for 30 min.Concentrate to ˜25 mL, dilute with saturated aqueous sodium bicarbonate,extract into ethyl acetate, combine and concentrate. Flashchromatography gives the titled compound (0.25 g, 42%). MS ES⁺ m/e295.8, 297.8 (M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 7.54 (d,J=10 Hz, 1H), 7.51 (s, 1H), 7.35 (d, J=10 Hz, 1H), 3.81 (s, 2H), 3.52(t, J=4 Hz, 1H), 2.35 (t,J=4 Hz, 4H).

Preparation 10 Preparation of2-(6-Bromo-imidazo[1,2-a]pyridin-3-yl)-1-morpholin-4-yl-ethanone

A. Preparation of (6-Bromo-imidazo[1,2-a]pyridin-3-yl)-acetic acid ethylester

Reflux a solution of 4,4-dimethoxy-but-2-enoic acid ethyl ester (3.3 g,19.12 mmol) and toluene-4-sulfonic acid (0.02 g, 0.12 mmol) in asolution of 2:1 acetonitrile:water (90 mL) for 30 min. Add2-amino-5-bromo-pyridine (1.65 g, 9.56 mmol) and reflux for 15 h. Cooland concentrate to ˜20 mL. Dilute the reaction with saturated aqueoussodium bicarbonate and extract into ethyl acetate. Combine andconcentrate organic extracts. Flash chromatography using ethylacetate/dichloromethane/methanol mixtures gives the subtitled compoundas a brown oil (2.9 g). TOF MS ES+ exact mass calculated forC₁₁H₁₁BrN₂O₂ (p+1): m/z=283.0075 Found: 283.0082. ¹H NMR (400 MHz,DMSO-d₆) δ 8.68 (s, 1H), 7.55 (d, J=10 Hz, 1H), 7.49 (s, 1H), 7.34 (d,J=10 Hz, 1H), 4.15 (s, 2H), 4.09 (q, J=4 Hz, 2H), 1.18 (t, J=4 Hz, 3H).EA Calcd. For C₁₁H₁₁BrN₂O₂: C, 46.66; H, 3.92; N, 9.89; Found C, 46.56;H, 4.02; N, 9.60.

B. Preparation of2-(6-Bromo-imidazo[1,2-a]pyridin-3-yl)-1-morpholin-4-yl-ethanone

Add 0.5M diisobutylaluminum hydride in toluene (4.6 mL, 2.29 mmol) to asolution of (6-bromo-imidazo[1,2-a]pyridin-3-yl)-acetic acid ethyl ester(0.65 g, 2.29 mmol) and morpholine (5 mL) in THF (40 mL) at −78° C.Gently warm the reaction to room temperature and dilute carefully withmethanol. Filter and concentrate the filtrate. Flash chromatographygives the subtitled compound (0.24 g, 32%) as a white solid. MS ES⁺ m/e324.0, 326.0 (M+1).

Preparation 11 Preparation of2-(6-Bromo-imidazo[1,2-a]pyridin-2-yl)-1-morpholin-4-yl-ethanone

A. Preparation of (6-Bromo-imidazo[1,2-a]pyridin-2-yl)-acetic Acid EthylEster

Add 4-bromo-3-oxo-butyric acid ethyl ester (12.08 g, 57.8 mmol) to asolution of 2-amino-5-bromo pyridine (5.0 g, 28.9 mmol) in acetonitrile(80 mL). Reflux for 4 days and concentrate to dryness. Purify by flashchromatography using appropriate ethyl acetate/methanol mixtures to givethe subtitled compound (5.75 g, 70%) as a brown oil. TOF MS ES+ exactmass calculated for C, HI BrN₂O₂ (p+1): m/z=283.0082 Found: 283.0084. ¹HNMR (400 MHz, DMSO-d₆) δ 8.68 (m, 1H), 7.82 (s, 1H), 7.45 (d, J=10 Hz,1H), 7.30 (dd, J=10, 2.0 Hz, 1H), 4.08 (q, J=7.0 Hz, 2H), 3.77 (s, 2H),1.18 (t, J=7.0 Hz, 3H).

B. Preparation of2-(6-Bromo-imidazo[1,2-a]pyridin-2-yl)-1-morpholin-4-yl-ethanone

Add 2M trimethylaluminum in toluene (1.94 mL, 3.88 mmol) to a solutionof morpholine (0.34 g, 3.88 mmol) in dichloromethane (10 mL). Stir for10 min and add a solution of (6-bromo-imidazo[1,2-a]pyridin-2-yl)-aceticacid ethyl ester (1.1 g, 3.88 mmol) in dichloromethane (12 mL). Heat at40° C. for 1 h, carefully dilute with saturated aqueous ammoniumchloride and extract into dichloromethane. Concentration followed byfiltration gives the titled compound (0.55 g, 43%) as a white solid. TOFMS ES+ exact mass calculated for C₁₃H₁₄BrN₃O₂ (p+1): m/z=324.0348;Found: 324.0330. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (m, 1H), 7.77 (s, 1H),7.45 (d, J=10 Hz, 1H), 7.29 (dd, J=10, 2.0 Hz, 1H), 3.81 (s, 2H),3.55-3.4 (m, 8H).

Preparation 12 Preparation of6-Bromo-imidazo[1,2-a]pyridine-3-carboxylic acid(2-dimethylamino-ethyl)-amide

A. Preparation of 6-Bromo-imidazo[1,2-a]pyridine-3-carboxylic acid ethylester

Add concentrated sulfuric acid (0.56 g, 5.78 mmol) to a suspension of2-chloro-3-oxo-propionic acid ethyl ester potassium salt (Tetrahedron2000, 58(40), 7915-7921; 3.27 g, 17.3 mmol) and 2-amino-5-bromopyridine(1.0 g, 5.78 mmol) in ethanol (100 mL). Reflux for 2 h, cool, andcarefully dilute with saturated aqueous sodium bicarbonate. Extract inethyl acetate, combine organic extracts, and concentrate. Flashchromatography using appropriate ethyl acetate/methanol mixtures gives0.85 g (55%) of the subtitled compound as a white solid. MS ES⁺m/e269.0, 271.0 (M+1) bromine isotope. ¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (m,1H), 8.28 (s, 1H), 7.79 (d, J=10 Hz, 1H), 7.70 (dd, J=10, 2 Hz, 1H),4.36 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H).

B. Preparation of 6-Bromo-imidazo[1,2-a]pyridine-3-carboxylic acid(2-dimethylamino-ethyl)-amide

Add 6-bromo-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (0.11g, 0.41 mmol) to a sealed tube containingN,N-dimethyl-ethane-1,2-diamine (5 mL). Heat the reaction at 150° C. for24 h. Flash chromatography using appropriate mixtures ofdichloromethane/2M ammonia in methanol gives 0.14 g of the product as ayellow oil. This material is progressed further withoutcharacterization. MS ES⁻ m/e 269.0, 311.0 (M−1).

Preparation 13 Preparation of 6-Iodo-imidazo[1,2-a]pyridine-2-carboxylicacid ethyl ester

Add 3-bromo-2-oxo-propionic acid ethyl ester (1.75 g, 9.09 mmol) to asolution of 2-amino-5-iodo pyridine (Tetrahedron 2002, 58, 2885-2890;1.0 g, 4.54 mmol) in acetonitrile (100 ml). Reflux for 12 h, concentrateto ˜30 ml, and dilute with saturated aqueous sodium bicarbonate. Extractinto dichloromethane, combine organic extracts, dry over anhydrousmagnesium sulfate, and concentrate. Titurate the residue in diethylether and filter to give 0.8 g (56%) of the subtitled compound as anoff-white solid. TOF MS ES+ exact mass calculated for C₁₀H₉₁N₂O₂ (p+1):m/z=316.9787; Found: 316.9784. ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (m, 1H),8.46 (s, 1H), 7.57-7.49 (m, 2H), 4.32 (q, T 7.0 Hz, 2 Hz), 1.33 (t,J=7.0 Hz, 3H).

Preparation 14 Preparation of 6-Iodo-imidazo[1,2-a]pyridine-3-carboxylicacid ethyl ester

Reflux a solution of 3-oxo-propionic acid ethyl ester (J. Med. Chem.2001, 44(12), 1193-2003; 3.4 g, 23.7 mmol) and 2-amino-5-iodopyridine in1:1 acetonitrile/ethanol (100 mL) overnight. Dilute with saturatedaqueous sodium bicarbonate, extract into dichloromethane (4×100 mL),combine organics, and concentrate. Flash chromatography usingappropriate ethyl acetate/hexane mixtures gives 3.7 g (78%) of thesubtitled compound as an off-white solid. ES⁺ m/e 316.7 (M+1).

Preparation 15 Preparation of 6-Bromo-8-fluoro-imidazo[1,2-a]pyridine

Prepared in a manner similar to Example 14, Part A. ¹H NMR (400 MHz,DMSO-d₆) δ 8.8 (d, J=1, 1H), 8.03 (dd, J=3,1, 1H), 7.63 (d, J=1 Hz, 1H),7.4 (dd, J=11, 1 Hz, 1H.

Preparation 15a Preparation of (5-Iodopyridin-2-yl)-methylene-amine

Add trifluoroacetic acid (3 drops) to a suspension of2-amino-5-iodopyridine (1.0 g, 4.5 mmol) and paraformaldehyde (1.0 g).Heat the mixture at reflux for 15 h and concentrate. Purification byflash chromatography eluting with ethyl acetate gives 0.8 g (75%) of thetitle compound as a white solid. ES⁺ m/e 232.6 (M+1).

Preparation 16 Preparation of(6-Iodo-imidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethyl-butyl)-amine

Add 1,1,3,3-tetramethylbutyl isocyanide (Aldrich; 0.57 g, 4.06 mmol) toa solution of (5-iodo-pyridin-2-yl)-methylene-amine (Preparation 15a;0.8 g, 3.4 mmol) in methanol (20 mL). Reflux for 36 h and concentrate.Purify by flash chromatography eluting with a gradient of 100% hexanesto 50% EtOAc/50% hexanes (45 mL/min, 44 min) giving 0.5 g (40%) of thetitle compound as a dark brown semi-solid. ES⁺ m/e 371.8 (M+1).

Preparation 17 Preparation ofN-Acetyl-N-(6-bromo-imidazo[1,2-a]pyridin-3-yl)-acetamide

Add trifluoroacetic acid (10 ml) to a solution of(6-bromo-imidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethyl-butyl)-amine(prepared in a manner similar to Preparation 12; 0.5 g, 1.54 mmol).Reflux for 1 h and concentrate to dryness. Flash chromatography usingethyl acetate/methanol mixtures gives the off-white solid intermediate6-bromo-imidazo[1,2-a]pyridin-3-ylamine ES⁺ m/e 213.6 (bromine isotopes)(M+1). Immediately dissolve intermediate in dichloromethane and addpyridine (1 g, 12.64 mmol) followed by acetic anyhydride (1.5 g, 14.69mmol) and reflux for 14 h. Concentration followed by purification byflash chromatography gives 0.38 g (83%) of the title compound. ES⁺ m/e297.7 (bromine isotopes) (M+1).

Preparation 18

Alternate Preparation of 3-Boronicacid-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Dissolve3-bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(20 g, 72 mmol) in dry THF (700 mL). Cool the solution to −75° C. undernitrogen. Add 2.5M n-butyllithium in hexanes (70 ml, 150 mmol) to thesolution over 30 min. maintaining the temperature under −65° C. Stir thesolution for 30 min. and add triisopropyl borate (Aldrich; 80 mL, 350mmol) to the mixture over 20 min. Stir for 30 min., then allow themixture to warm to room temperature over 3 h. Dilute the reaction with300 mL of staturated ammonium chloride and stir for 2 h. Evaporate someof the solvent and dilute the crude product with 3:1Chroloform/isopropyl alcohol (2 L). Wash organic layer with brine (500mL×3), over sodium sulfate, and evaporate the solvent to give the titledcompound (15.5 g, 87%) as a pale yellow solid. MS (electrospray, m/z)244 (M+1).

Preparation 19 Preparation of 3-Boronicacid-2-(6-pentyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

The title compound was obtained as a by-product from preparation 18.

Preparation 20

Alternate Preparation of 3-Boronicacid-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo [1,2-b]pyrazole

Prepare using identical procedures to that used in Preparation 18 exceptemploying3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole.

Preparation 21a 2-Ethoxycarbonylmethoxy-5-iodo-benzoic acid methyl ester

Reflux a mixture of 2-hydroxy-5-iodo-benzoic acid methyl ester (TCI; 5.5g, 20 mmol) and ethyl bromoacetate (Aldrich; 6.7 g, 40 mmol) in acetone(60 mL) in the presence of potassium (5.5 g, 40 mmol) for 3 h. Filterout the solid and evaporate acetone to give a white residue. Dissolvethe residue in ethyl acetate and wash with brine. Evaporate the solventin vacuum to give final product as a white solid (7 g, 96%). MS(electrospray, m/z) 365 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 8.1 (d, J=2.0Hz, 1H), 7.70 (dd, J=8.8, 2.8 Hz, 1H), 6.6 (d, J=8.8 Hz, 1H), 4.68 (s,2H), 4.3 (q, J=6.8 Hz, 2H), 3.9 (s, 1H), 1.3 (t, J=6.8 Hz, 3H).

Preparation 21b Acetic acid 5-Iodobenzofuran-3-yl ester

Place 2-carboxymethoxy-5-iodo-benzoic acid (Preparation 21a; 7 g, 21mmol) acetic anhydride (35 ml), sodium acetate (4 g), and acetic acid (5mL) into a 50 mL round bottom flask. Heat the resulting mixture at 140°C. under stirring for 5 h and cool to room temperature. Add water (12mL) into the mixture gradually maintaining the temperature below 60° C.and continue to stir for 18 h. Dilute with water (200 mL) and collectthe resulting precipitate via vacuum filtration. Wash the solid withwater and dry to give the final product (6 g, 95%). MS (electrospray,m/z) 303 (M+1).

Preparation 22 Preparation of a Mixture of6-Iodo-1-methyl-1H-benzoimidazole and 5-Iodo-1-methyl-1H-benzoimidazole

Stir 5-iodo-1H-benzoimidazole (U.S.S.R. 1616911, 30 Dec. 1990; 2.1 g,8.6 mmol), iodomethane (1.6 mL, 25.8 mmol), and sodium hydride (0.62 g,26.0 mmol) in DMF (20 mL) at room temperature for 2 h. Extract theproduct with 3:1 chloroform/isopropyl alcohol and wash the organic phasewith saturated sodium chloride. Dry over sodium sulfate to give thedesired product as a dark yellow solid (2.13 g, 96%). MS (electrospray,m/z) 259.0 (M+1).

Preparation 23 Preparation of a Mixture of6-Iodo-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole and5-Iodo-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole

Stir 5-iodo-1H-benzoimidazole (U.S.S.R. pat. 1616911, 30 Dec. 1990; 2.0g, 8.2 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (4.0 mL, 26.5 mmol),sodium hydride (0.78 g, 32.8 mmol) in DMF (20 m]L) at room temperaturefor 2 h. Extract the product with 3:1 chloroform/isopropyl alcohol andwash with saturated sodium chloride. Dry the organic phase over sodiumsulfate and filter to give a dark yellow oil. Purify by silica gel flashchromatography eluting with dichloromethane to 10% THF/90%dichloromethane to afford a light yellow oil as a mixture of the twotitled compounds (2.59 g, 83%). MS (electrospray, m/z) 387.1 (M+1).

Preparations 24 and 25 Preparation of a Mixture of5-Iodo-benzoimidazole-1-carboxylic acid tert-butyl ester and6-Iodo-benzoimidazole-1-carboxylic acid tert-butyl ester

Add di-tert-butyl dicarbonate (0.37 g, 1.7 mmol) and DMAP (20 mg, 0.16mmol) to a solution of 5- and 6-iodobenzimidazole (Rabiger, D. J.;Jouilie, M. M.; J. Org. Chem. 1961, 26, 1649; 0.38 g, 1.6 mmol) indioxane (7.5 mL). Stir the reaction mixture for 17 h. AddN,N-dimethylethylenediamine (0.3 mL). Dilute the reaction mixture withethyl acetate and wash the organic layer with 0.1N aqueous hydrochloricacid and brine. Concentrate in vacuo and purify by flash columnchromatography, using an appropriate mixture of ethyl acetate/hexanes,to provide the subtitled compound as a 2:3 mixture of two regioisomers(136 mg, 25%).

Minor isomer: MS (ESI) m/e=345 (M+1). ¹H NMR (CDCl₃) δ 8.36 (s, 1H),8.13 (d, J=1 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.67 (dd, J=8, 1 Hz, 1H),1.70 (s, 9H). TLC (SiO₂): R_(f)0.7 (1:1 ethyl acetate/hexanes). Majorisomer: MS (ESI) m/e=345 (M+1). ¹H NMR (CDCl₃) δ 8.40 (d, J=2 Hz, 1H),8.33 (s, 1H), 7.65 (dd, J=9, 2 Hz, 1H), 7.53 (d, J=9 Hz, 1H), 1.70 (s,9H). TLC (SiO₂): R_(f)0.6 (1:1 ethyl acetate/hexanes).

Preparation 26 Preparation of 7-Bromo-2-chloro-quinoxaline

Heat benzene-1,2-diamine (7.5 g, 69 mmol) and oxo-acetic acid ethylester (20 mL) in ethanol (100 mL) at 120° C. for 18 h. Cool, filter theresulting precipitate, and wash with dry ether to give1H-quinoxalin-2-one (6.7 g). Dissolve 1H-quinoxalin-2-one in acetic acid(300 mL), add bromine (5 mL), and stir the reaction mixture for 1 h.Filter the resulting crystals and wash with ether to afford7-bromo-1H-quinoxalin-2-one (7.2 g). Reflux 7-bromo-1H-quinoxalin-2-onein POCl₃ (30 mL) for 18 h. Remove POCl₃ in vacuo, dissolve the productin 3:1 chloroform/isopropyl alcohol, and wash the organic phase withsaturated sodium bicarbonate. Dry over sodium sulfate and purify bysilica gel flash chromatography eluting with dichloromethane to 10%methanol/90% dichloromethane to afford the title compound as a yellowsolid (4.5 g, 58%). MS (electrospray, m/z) 243.0 and 245.0 (M+1).

Preparation 27 Preparation of 2-(7-Bromo-quinoxalin-2-yloxy)-ethanol

Suspend sodium hydride (310 mg, 13 mmol) in a solution of ethyleneglycol (800 mg, 13 mmol) in DMF (50 mL) at 0° C. After stirring for 30min at room temperature, 7-bromo-2-chloro-quinoxaline (Preparation 26;610 mg, 2.5 mmol) is added. Stir for 2 h at room temperature and dilutewith 3:1 chloroform/isopropyl alchol. Wash the organic phase with brineand purify by FCC to give the title compound (564 mg, 85%). MS m/e (268,M+1). ¹H NMR (400 MHz, CDCl₃) δ 8.5 (s, 1H), 8.0 (d, J=2.0 Hz), 7.90(dd, J=8.8, 2.0 Hz, 1H), 7.7 (d, J=8.8 Hz, 1H), 4.6 (t, d=4.8 Hz, 2H),43.9 (t, J=4.8 Hz, 2H).

Preparation 28 Preparation of 6-Bromobenzothiazole

Add anhydrous copper (II) bromide (1.79 g, 7.99 mmol), tert-butylnitrite (1.2 mL, 9.98 mmol) and anhydrous acetonitrile (20 mL) to around bottom flask fitted with a reflux condenser and an additionfunnel. Heat at 65° C. for 10 min. Add a solution ofbenzothiazol-6-ylamine (Lancaster; 1 g, 6.66 mmol) in acetonitrile (10mL) over a period of 5 min via addition funnel. Stir at 65° C. for 30min. Cool to room temperature, pour into 20% aqueous hydrochloric acid(100 mL), and extract with ether (2×100 mL). Wash the organic layer with20% aqueous hydrochloric acid. Dry the organic phase with sodiumsulfate, filter, evaporate and chromatograph (10% ethyl acetate/90%hexanes) to give the title product (0.4 g, 29%) as a pale yellow solid.MS (ESI) m/e 215 (M+1). ¹H NMR (CDCl₃): δ 8.95 (s, 1H), 8.10-8.06 (m,1H), 8.00-7.94 (m, 1H), 7.65-7.56 (m, 1H). TLC (SiO₂): R_(f)0.23 (50%ethyl acetate/50% hexanes).

Preparation 29 Preparation of 5-Iodo-pyrazolo[1,5-a]pyrimidine

Dissolve 5-chloro-pyrazolo[1,5-a]pyrimidine (Hans Reimlinger et al.,Chem. Ber. 1970, 103, 3252-3265; 1.15 g, 7.5 mmol) and sodium iodide(5.6-g, 37.4 mmol) in anhydrous acetonitrile (50 mL). Add acetylchloride (2.7 ml, 37.9 mmol). Stir and reflux under nitrogen for 20 h.Pour the reaction mixture into a stirring mixture of 0.5M aqueouspotassium carbonate (200 mL), 1.0M aqueous sodium sulfite (50 mL), anddiethyl ether (350 mL). Separate the organic layer, dry over anhydrousmagnesium sulfate, filter and concentrate under reduced pressure.Chromatograph the crude product on flash silica using neatdichloromethane to obtain 950 mg (51%) of the title compound as a yellowsolid. TOF MS ES+ exact mass calculated for C₆H₄N₃₁₀): m/z=245.9528;Found: 245.9517. ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (d, J=7 Hz, 1H), 8.18(d, J=2 Hz, 1H), 7.32 (d, J=7 Hz, 1H), 6.69 (d, J=2 Hz, 1H).

Preparation 30 General Suzuki Coupling Method A

Add the heteroaryl halide (1-1.2 eq) and THF (0.2 M) to a round-bottomflask under argon. Purge the solution with argon for 10 min. Addtris(dibenzylideneacetone) dipalladium(0) (Strem; 0.1 eq) andbis[1,2-bis(diphenylphosphino)ethane]palladium(0) (Strem; 0.1 eq). Purgethe reaction with argon for 2 min and stir at room temperature for 20min. Add2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid or2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid (1.0 eq) in THF (0.3 M). Stir the reaction mixture for 10 min. Add2M aqueous potassium carbonate (2.4 eq). Heat the reaction to 40° C. Addadditional tris(dibenzylideneacetone) dipalladium(0) (0.1 eq) after 1.5h and again after 3 h. Continue heating the reaction for ˜15 hr. Coolthe reaction mixture to room temperature and concentrate in vacuo.Purify by SCX resin, eluting with 2M ammonia in methanol, followed byflash column chromatography (silica gel, eluting with the appropriatemixture of methylene chloride/chloroform/methanol/concentrated aqueousammonium hydroxide). Concentrate in vacuo to provide the final compound.

Preparation 31 General Suzuki Coupling Method B

Add 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid (1.0 eq), the hetroaryl halide (1.2 eq), cesium carbonate (2.0 eq),and THF (0.2M) to a round-bottom flask under argon. Purge the solutionwith argon for 10 min. Add tris(dibenzylideneacetone) dipalladium (0)(Strem; 0.1 eq.) and 1,3-bis(2,6-di-1-propylphenyl) imidazolium chloride(Strem; 0.2 eq.). Heat the reaction to 60° C. Add additionaltris(dibenzylideneacetone) dipalladium (0) (0.1 eq.) and1,3-bis(2,6-di-1-propylphenyl) imidazolium chloride (0.2 eq.) after 3 h.Stir the reaction mixture at 60° C. for ˜15 h. Cool the reaction to roomtemperature and concentrate in vacuo. Purify by SCX resin, eluting with2M ammonia in methanol, followed by flash column chromatography (silicagel, eluting with the appropriate mixture of methylenechloride/chloroform/methanol/concentrated aqueous ammonium hydroxide).Concentrate in vacuo to provide the final compound.

Preparation 32 General Suzuki Coupling Method C

Add 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid (1.0 eq), the hetroaryl halide (1.0-1.2 eq), sodium bicarbonate(2.0 eq), tetrakis(triphenylphosphine) palladium (0) (Strem; 0.02-0.05eq), acetonitrile (0.1M), and water (0.1M) to a microwave reactorvessel. Seal the reactor vessel and irradiate with microwave radiationfor 15 min at 110° C. Cool the reaction mixture to room temperature.Extract the reaction mixture with chloroform (3×25 mL), dry the combinedextracts with sodium sulfate, and concentrate in vacuo. Purify by flashcolumn chromatography (silica gel, eluting with the appropriate mixtureof methylene chloride/chloroform/methanol/concentrated aqueous ammoniumhydroxide) and concentrate in vacuo to provide the final compound.

Preparation 33 General Suzuki Coupling Method D

Add 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid (1.0 eq), the hetroaryl halide (1.0-1.2 eq), sodium bicarbonate(2.0 eq), tetrakis(triphenylphosphine)palladium(0) (Strem; 0.02-0.05eq), acetonitrile (0.1M), and water (0.1M) to a round-bottom flask. Heatthe reaction to 85° C. for 1-2 h. Cool the reaction mixture to roomtemperature. Extract the reaction mixture with chloroform (3×25 mL), drythe combined extracts with sodium sulfate, and concentrate in vacuo.Purify by flash column chromatography (silica gel, eluting with theappropriate mixture of methylenechloride/chloroform/methanol/concentrated aqueous ammonium hydroxide)and concentrate in vacuo to provide the final compound.

EXAMPLE 1 Preparation of2-(Pyridin-2-yl)-3-(thiophen-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Add 3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation 4, 250 mg, 0.95 mmol) and anhydrous THF (2.5 mL) to a roundbottom flask under nitrogen atmosphere. Purge the reaction flask withnitrogen for 10 min. Add tris(dibenzylideneacetone)dipalladium(0) (87mg, 0.095 mmol) and bis(1,2-bis(diphenylphosphino)ethane) palladium(0)(86 mg, 0.095 mmol) to the reaction flask, purge with nitrogen for 2min, and then stir at room temperature for 20 min. Addthiophene-2-boronic acid (Maybridge; 120 mg, 0.95 mmol) in DMF (1 mL) tothe reaction and stir for 10 min. Add 2M aqueous potassium carbonate(1.11 mL, 2.3 mmol) and heat the reaction mixture to 65° C. Addadditional tris(dibenzylideneacetone) dipalladium(0) (87 mg, 0.095 mmol)to the reaction after 1 h, 3 h, and 5 h. Heat the reaction for a totalof 20 h, cool to room temperature, and filter through Celite® withchloroform/methanol (250 mL, 1:1 ratio). Concentrate in vacuo and purifyby flash column chromatography to provide the title compound (13 mg, 5%)as a pale, yellow solid. MS ESI+ m/e 268 (M+1). ¹H NMR (CDCl₃) δ8.80-8.72 (m, 1H), 7.80-7.56 (m, 2H), 7.31-7.20 (m, 2H), 7.12-7.03 (m,1H), 7.01-6.95 (m, 1H), 4.31-4.19 (m, 2H), 3.11-3.05 (m, 2H), 2.79-2.60(m, 2H). HPLC: 98.0%, R_(t)=15.25 min. TLC (SiO₂): R_(f)0.4 (5:95methanol/dichloromethane).

EXAMPLE 2 Preparation of5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole

In a similar fashion to Example 1, react 1H-indole-5-boronic acid(Fluka; 150 mg, 0.95 mmol) with3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation 4; 250 mg, 0.95 mmol) to provide the title compound (10 mg,4%) as an off-white solid. MS ESI+ m/e 301 (M+1). ¹H NMR (CDCl₃) δ8.67-8.58 (m, 1H), 7.61 (s, 1H), 7.52-7.45 (m, 1H), 7.39-7.29 (m, 2H),7.21-7.16 (m, 1H), 7.14-7.04 (m, 2H), 6.52-6.48 (m, 1H), 4.31-4.21 (m,2H), 3.06-2.98 (m, 2H), 2.73-2.60 (m, 2H). TLC (SiO₂): R_(f) 0.4 (1:3[80:18:2 chloroform/methanol/concentrated aqueous ammoniumhydroxide]/dichloromethane).

EXAMPLE 3 Preparation of3-(2-Phenyl-oxazol-5-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

In a similar fashion to Example 1, react 5-bromo-2-phenyloxazole(Combi-Blocks; 120 mg, 0.52 mmol) with2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5; 120 mg, 0.52 mmol) to provide the title compound (20 mg,12%) as a white solid. MS ESI+ m/e 329 (M+1). ¹H NMR (CDCl₃) δ 8.78-8.70(m, 1H), 8.05-7.99 (m, 2H), 7.95-7.89 (m, 1H), 7.82 (s, 1H), 7.81-7.70(m, 1H), 7.50-7.41 (m, 3H), 7.30-7.25 (m, 1H), 4.31-4.21 (m, 2H),3.38-3.24 (m, 2H), 2.82-2.66 (m, 2H). HPLC: 97.2%, R_(t)=16.67 min. TLC(SiO₂): R_(f)0.3 (1:3 [80:18:2 chloroform/methanol/concentrated aqueousammonium hydroxide]/dichloromethane).

EXAMPLE 4 Preparation of4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzo[2,1,3]thiadiazole

Add 4-iodo-[2,1,3]-benzothiadiazole (Maybridge; 350 mg, 1.3 mmol),2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5; 300 mg, 1.3 mmol), potassium fluoride (250 mg, 4.3mmol), and THF (6.0 mL) to a flask under nitrogen. Purge the system withnitrogen for 10 min and add tris(dibenzylideneacetone) dipalladium(0)(120 mg, 0.13 mmol) and tri-tert-butylphosphonium tetrafluoroborate(Strem; 100 mg, 0.039 mmol). Purge the system with nitrogen for 2 minand stir for 48 h at 45° C. Filter the reaction through Celite®, rinsewith chloroform/methanol, and concentrate in vacuo. Purify by flashcolumn chromatography followed by reverse-phase preparative HPLC.Collect the pure fractions from the HPLC, concentrate in vacuo, take upthe residue in methanol, and treat with MP-carbonate beads. Filter andconcentrate in vacuo to provide the title compound (46 mg, 11%) as apale yellow solid. Melting Range: 140-142° C. MS APCI m/e 320 (M+1). ¹HNMR (CDCl₃): δ 8.44-8.37 (m, 1H), 7.95-7.89 (m, 1H), 7.60-7.49 (m, 3H),7.48-7.41 (m, 1H), 7.12-7.02 (m, 1H), 4.37-4.28 (m, 2H), 3.09-2.99 (m,2H), 2.72-2.60 (m, 2H). HPLC: 98.3%, R_(t)=15.03 min. TLC (SiO₂):R_(f)0.3 (1:1 [80:18:2 chloroform/methanol/concentrated aqueous ammoniumhydroxide]/dichloromethane).

EXAMPLE 5 Preparation of5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]benzo[2,1,3]thiadiazole

In a similar fashion to Example 4, react5-bromo-[2,1,3]-benzothiadiazole (Maybridge; 180 mg, 0.83 mmol) with2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5; 190 mg, 0.83 mmol) to provide the title compound (65 mg,16%) as a tan solid. Melting Range: 184-186° C. MS ESI+ m/e 320 (M+1).¹H NMR (CDCl₃) δ 8.61-8.52 (m, 1H), 7.94 (s, 1H), 7.89-7.82 (m, 1H),7.70-7.62 (m, 2H), 7.52-7.49 (m, 1H), 7.29-7.17 (m, 1H), 4.33-4.22 (m,2H), 3.12-3.02 (m, 2H), 2.72-2.60 (m, 2H). HPLC: >99%, R_(t)=15.41 min.TLC (SiO₂): R_(f)0.3 (1:1 [80:18-2 chloroform/methanol/concentratedaqueous ammonium hydroxide]/dichloromethane).

EXAMPLE 6 Preparation of6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline

Add THF (2.2 mL) to 6-bromo-quinoxaline (Yamamoto, T. et al., J. Am.Chem. Soc. 1996, 118, 3930-3936; 219 mg, 1.05 mmol) and purge thesolution with nitrogen for 10 min. Addtris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.087 mmol) andbis(1,2-bis(diphenylphosphino)ethane)palladium(0) (78 mg, 0.087 mmol),purge the reaction with nitrogen for 2 min, and stir the reaction atroom temperature for 20 min. Add(2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5; 200 mg, 0.87 mmol) in 1:1 DMF/THF (2 mL each) and stirfor 10 min. Add 2.0M aqueous potassium carbonate (1.04 mL, 2.1 mmol) andheat the reaction to 65° C. Add additionaltris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.087 mmol) after 1 hand 3 h. Stir the reaction at 65° C. for 18 h, filter through Celite®with methanol/chloroform, and concentrate in vacuo. Purify by flashcolumn chromatography followed by reverse-phase preparative HPLC.Concentrate the pure fractions from the preparative HPLC in vacuo, takeup in methanol, treat with MP-carbonate beads, filter, and concentratein vacuo to provide the title compound (82 mg, 30%) as a clear,colorless oil. MS ESI+ m/e 314 (M+1). ¹H NMR (CDCl₃) δ 8.86 (m, 3H),8.11 (m, 1H), 8.05 (m, 2H), 7.79 (m, 2H), 7.47 (m, 1H), 4.33 (m, 2H),3.11 (m, 2H), 2.72 (m, 2H). HPLC: 98.5%, R_(t)=13.61 min. TLC (SiO₂):R_(f)0.3 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammoniumhydroxide]/dichloromethane).

EXAMPLE 7 Preparation of5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline

A. Preparation of Trifluoro-methanesulfonic Acid Quinoxalin-5-yl Ester

Add trifluoromethanesulfonic anhydride (0.66 mL, 3.94 mmol) to asolution of quinoxalin-5-ol (Yamamoto, T. et al., J. Am. Chem. Soc.1996, 118, 3930-3936; 500 mg, 3.42 mmol) in pyridine (6.8 mL) at 0° C.Allow the reaction to warm slowly to room temperature over 18 h. Addsaturated aqueous sodium bicarbonate solution (100 mL) and extract themixture with methylene chloride (3×100 mL). Dry the combined organicsolutions with sodium sulfate, concentrate in vacuo, and purify by flashcolumn chromatography to provide the subtitled compound (810 mg, 85%) asan off-white solid. MS ESI+ m/e 279 (M+1). ¹H NMR (CDCl₃): δ 8.85 (m,2H), 8.18 (m, 1H), 7.84 (m, 1H), 7.63 (m, 1H). TLC (SiO₂): R_(f)0.2 (3:1hexanes/ethyl acetate).

B. Preparation of5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline

Add THF (2.2 mL) to trifluoro-methanesulfonic acid quinoxalin-5-yl ester(292 mg, 1.05 mmol) and purge the solution with nitrogen for 10 min. Addtris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.087 mmol) andbis(1,2-bis(diphenylphosphino)ethane)palladium(0) (78 mg, 0.087 mmol),purge the reaction with nitrogen for 2 min, and stir the reaction atroom temperture for 20 min. Add2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5; 200 mg, 0.87 mmol) in 1:1 DMF/THF (2 mL) and stir for 10min. Add 2.0M aqueous potassium carbonate (1.04 mL, 2.1 mmol) and heatthe reaction to 65° C. Add additionaltris(dibenzylideneacetone)dipalladium(0) (80 mg, 0.087 mmol) after 1 hand 3 h. Stir the reaction at 65° C. for 18 h, filter through Celite®with methanol/chloroform, and concentrate in vacuo. Purify by flashcolumn chromatography followed by reverse-phase preparative HPLC.Concentrate the pure fractions from the preparative HPLC in vacuo, takeup in methanol, treat with MP-carbonate beads, filter, and concentratein vacuo to provide the title compound (11 mg, 7%) as a clear, colorlessoil. MS APCI+ m/e 314 (M+1). ¹H NMR (DMSO-d₆) δ 8.78 (m, 1H), 8.68 (m,1H), 8.54 (m, 1H), 8.08 (m, 1H), 7.72 (m, 3H), 7.53 (m, 1H), 7.22 (m,1H), 4.37 (m, 2H), 2.95 (m, 2H), 2.64 (m, 2H). HPLC: 98.6%, R_(t)=13.5min. TLC (SiO₂): R_(f)0.2 (1:3 [80:18:2 chloroform/methanol/concentratedaqueous ammonium hydroxide]/dichloromethane).

EXAMPLE 8 Preparation of2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-imidazo[4,5-b]pyridine

Add 2,3-diaminopyridine (Fluka; 120 mg, 1.09 mmol) and phosphorousoxychloride (4.4 mL) to2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid(Preparation 3; 251 mg, 1.09 mmol) and heat the reaction at 106° C. for3 h. Cool the reaction to 0° C. and add 1N aqueous hydrochloric acid (10mL) slowly and stir for 10 min. Neutralize the mixture with saturatedaqueous sodium bicarbonate and extract with chloroform. Wash thecombined organic layers with brine, dry with sodium sulfate, concentratein vacuo, purify by flash column chromatography, and triturate withhexanes to provide the title compound (159 mg, 48%) as a tan solid. Mp170-172° C. MS ESI+ m/e 303 (M+1). ¹H NMR (CDCl₃) δ 8.80 (br, 1H), 8.34(m, 2H), 7.88 (m, 2H), 7.36 (m, 1H), 7.11 (m, 1H), 4.29 (m, 2H), 3.54(m, 2H), 2.71 (m, 2H). HPLC: 96.3%, R_(t)=13.59 min. TLC (SiO₂):R_(f)0.3 (1:3 [80:18:2 chloroform/methanol/concentrated aqueous ammoniumhydroxide]/dichloromethane).

EXAMPLE 9 Preparation of2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-imidazo[4,5-c]pyridine

In a similar fashion to Example 8, react 3,4-diaminopyridine(commercially available e.g. Fluka; 120 mg, 1.1 mmol) and phosphorousoxychloride (4.4 mL) with2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid(Preparation 3; 250 mg, 1.1 mmol) to provide the title compound (30 mg,10%) as a tan solid. Mp 201-203° C. MS ESI+ m/e 303 (M+1). ¹H NMR(DMSO-d₆) δ 9.02 (m, 1H), 8.75 (m, 1H), 8.31 (m, 2H), 7.90 (m, 1H), 7.65(m, 1H), 7.41 (m, 2H), 4.29 (m, 2H), 3.51 (m, 2H), 2.77 (m, 2H). HPLC:94.6%, R_(t)=12.6 min. TLC (SiO₂): R_(f)0.3 (1:1 [80:18:2chloroform/methanol/concentrated aqueous ammoniumhydroxide]/dichloromethane).

EXAMPLE 10 Preparation of2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole

In a similar fashion to Example 8, react 1,2-phenylenediamine (Fluka;120 mg, 1.1 mmol) and phosphorous oxychloride (4.4 mL) with2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid(Preparation 3, 250 mg, 1.1 mmol) to provide the title compound (68 mg,21%) as a brown solid. Mp 172-175° C. MS ESI+ m/e 302 (M+1). ¹H NMR(CDCl₃) δ 8.78 (m, 1H), 8.30 (m, 1H), 7.86 (m, 1H), 7.71 (m, 1H), 7.55(m, 1H), 7.33 (m, 1H), 7.15 (m, 2H), 4.14 (m, 2H), 3.49 (m, 2H), 2.71(m, 2H). HPLC: 98.6%, R_(t)=16.89 min. TLC (SiO₂): R_(f)0.4 (1:1[80:18:2 chloroform/methanol/concentrated aqueous ammoniumhydroxide]/dichloromethane).

EXAMPLE 11 Preparation of2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-oxazolo[4,5-b]pyridine

In a similar fashion to Example 8, react 2-amino-3-hydroxypyridine(Fluka; 144 mg, 1.3 mmol) and phosphorous oxychloride (4.4 mL) with2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylic acid(Preparation 3; 250 mg, 1.1 mmol) to provide the title compound (74 mg,22%) as a tan solid. Mp 182-184° C. MS ESI+ m/e 304 (M+1). ¹H NMR(CDCl₃) δ 8.75 (m, 1H), 8.52 (m, 1H), 8.12 (m, 1H), 7.84 (m, 1H), 7.69(m, 1H), 7.32 (m, 1H), 7.15 (m, 1H), 4.31 (m, 2H), 7.37 (m, 2H), 2.75(m, 2H). HPLC: 98.3%, R_(t)=13.95 min. TLC (SiO₂): R_(f)0.4 (1:3[80:18:2 chloroform/methanol/concentrated aqueous ammoniumhydroxide]/dichloromethane).

EXAMPLE 12 Preparation of2-Dimethylamino-N-[6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,8]naphthyridin-2-yl]-acetamide

A. Preparation ofN-(6-Bromo-[1,8]naphthyridin-2-yl)-2-dimethylamino-acetamide

Add N,N-dimethylglycine (0.28 g, 2.68 mmol),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.47 g, 2.45 mmol),1-hydroxybenzotriazole (0.33 g, 2.45 mmol), and methylene chloride (111mL) to 6-bromo-[1,8]naphthyridin-2-ylamine (Reichardt, C. et al,Tetrahedron Lett. 1977, 2087; 0.50 g, 2.23 mmol). Stir the reaction atroom temperature for 19 h, concentrate in vacuo and purify by flashcolumn chromatography to provide the subtitled compound (0.41 g, 60%) asan orange solid. MS ESI+ m/e 309/311 (M+1). ¹H NMR (DMSO-d₆) δ 10.52 (m,1H), 8.96 (m, 1H), 8.71 (m, 1H), 8.35 (m, 2H), 3.15 (s, 2H), 2.25 (s,6H). TLC (SiO₂): R_(f)0.3 (1:4 [80:18:2 chloroform/methanol/concentratedaqueous ammonium hydroxide]/dichloromethane).

B. Preparation of2-Dimethylamino-N-16-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,8]naphthyridin-2-yl]-acetamide

Add N-(6-bromo-[1,8]naphthyridin-2-yl)-2-dimethylamino-acetamide (148mg, 0.48 mmol),2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5; 100 mg, 0.44 mmol), potassium fluoride (84 mg, 1.45mmol), and THF (1.5 mL) to a flask under nitrogen. Purge the system withnitrogen for 10 min and add tris(dibenzylideneacetone)dipalladium(0) (40mg, 0.044 mmol) and tri-tert-butylphosphonium tetrafluoroborate (Strem;25 mg, 0.088 mmol). Purge the system with nitrogen for 2 min then stirfor 16 h at room temperature. Add additionaltris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.054 mmol) andtri-tert-butylphosphonium tetrafluoroborate (40 mg, 0.138 mmol) and heatthe reaction to 65° C. for 9 h. Filter the reaction through Celite®,rinse with chloroform/methanol, and concentrate in vacuo. Purify byflash column chromatography followed by reverse-phase preparative HPLC.Collect the pure fractions from the HPLC, concentrate in vacuo, take upthe residue in methanol, and treat with MP-carbonate beads. Filter,concentrate in vacuo, and triturate with hexanes to provide the titlecompound (10 mg, 5%) as a tan solid. MS ESI+ m/e 414 (M+1). ¹H NMR(CDCl₃) δ 10.21 (m, 1H), 8.93 (m, 1H), 8.48 (m, 2H), 8.09 (m, 2H), 7.68(m, 2H), 7.20 (m, 1H), 4.27 (m, 2H), 3.17 (m, 4H), 2.72 (m, 2H), 2.41(s, 6H). HPLC: 95.1%, R_(t)=11.21 min. TLC (SiO₂): R_(f)0.3 (1:1[80:18:2 chloroform/methanol/concentrated aqueous ammoniumhydroxide]/dichloromethane)

EXAMPLE 13 Preparation of4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,8]naphthyridine

Add THF (1 mL) to 4-bromo-[1,8]naphthyridine (Barlin, G. B. and Tan,W-L. Australian J. Chem. 1984, 37, 1065-1073; 66 mg, 0.31 mmol) andpurge the solution with nitrogen for 10 min. Addtris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol) andbis(1,2-bis(diphenylphosphino)ethane) palladium(0) (24 mg, 0.026 mmol),purge the reaction mixture with nitrogen for 2 min, and stir thereaction at room temperature for 20 min. Add2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5, 60 mg, 0.26 mmol) in 1:1 DMF/THF (1 mL) and stir for 10min. Add 2.0 M aqueous potassium carbonate (0.32 mL, 0.63 mmol) and heatthe reaction to 40° C. Add additionaltris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol) after 1 hand 3.5 h. Stir the reaction at 40 DC for 24 h and concentrate in vacuo.Load the crude reaction mixture onto SCX resin with methanol, wash theresin with methanol (100 mL), and elute with methanolic ammonia solution(2M, 100 mL). Concentrate the ammonia fraction in vacuo, purify by flashcolumn chromatography and triturate with hexanes to provide the titlecompound (28.7 mg, 35%) as a tan solid. MS ESI+ m/e 314 (M+1). ¹H NMR(CDCl₃) δ 9.11 (m, 1H), 9.07 (m, 1H), 8.25 (m, 1H), 8.10 (m, 1H),7.35-7.50 (m, 3H), 7.04 (m, 2H), 4.38 (m, 2H), 2.88 (m, 2H), 2.70 (m,2H). HPLC: 94.8%, R_(t)=6.75 min. TLC (SiO₂): R_(f)0.3 (1:1 [80:18:2chloroform/methanol/concentrated aqueous ammoniumhydroxide]/dichloromethane).

EXAMPLE 14 Preparation of2-(Pyridin-2-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

A. Preparation of 6-Bromo-imidazo[1,2-a]pyridine

Reflux a solution of 2-amino-5-bromo-pyridine (Maybridge; 1.0 g, 5.78mmol), 50% aqueous chloroacetaldehyde (2 mL, 12.7 mmol) in acetonitrile(100 mL) for 14 h. Dilute the reaction with saturated aqueous sodiumbicarbonate and extract into ethyl acetate. Flash chromatography usingappropriate ethyl acetate/hexane mixtures gives 0.95 g (83%) of thesubtitled compound as a tan solid. MS (electrospray, m/z) 196.7, 198.7(M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 8.9 (d, J=1.5 Hz, 1H), 7.90 (s, 1H),7.58 (d, J=1.5 Hz, 1H), 7.53 (d, J=9.2 Hz, 1H), 7.29 (dd, J=9.2, 2 Hz,1H).

B. Preparation of2-(Pyridin-2-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Add tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.022 mmol) to amicrowave tube containing a solution of 6-bromo-imidazo[1,2-a]pyridine(0.086 g, 0.44 mmol),2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5; 0.1 g, 0.436 mmol), and 2M aqueous potassium carbonate(0.5 mL, 1 mmol) in dimethylsulfoxide (1.5 mL). Irradiate the reactionin a microwave reactor set at 111° C., 50 W., 10 min with internalcooling. Normal phase chromatography using ethyl acetate/methanolmixtures followed by reversed phase preparative chromatography gives the0.05 g (38%) of the title compound as a white solid. MS (electrospray,m/z) 301.9 (M+1). ¹H NMR (400 MHz, DMSO-d) δ 8.57 (s, 1H), 8.4 (d, J=4.8Hz, 1H), 7.87 (s, 1H), 7.78 (m, 2H), 7.52 (s, 1H), 7.42 (d, J=9.2 Hz,1H), 7.26 (m, 1H), 7.05 (dd, J=9.2, 2 Hz, 1H), 4.2 (t, J=6.6 Hz, 2H,2.99 (t, J=6.6 Hz, 2H), 2.59 (m, 1H).

EXAMPLE 14a Alternative preparation of2-(Pyridin-2-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

A. Preparation of 6-Iodo-imidazo[1,2-a]pyridine

Reflux a solution of 2-amino-5-iodo-pyridine (Tetrahedron 2002, 58,2885-2890; 1.5 g, 6.82 mmol) and 50% aqueous chloroacetaldehyde (1.56mL, 12.3 mmol) in acetonitrile (150 mL) for 14 h. Cool, concentrate, anddissolve the residue in 1:1 saturated aqueous sodiumbicarbonate/dichloromethane. Extract the aqueous layer withdichloromethane, combine the organic layers, and concentrate. Flashchromatography using appropriate ethyl acetate/methanol mixtures gives1.1 g (66%) of the subtitled compound as a light green solid. TOF MS ES⁺exact mass calculated for C₇H₅₁N₂ (p+1): m/z=244.9576; Found: 244.9564.¹H NMR (400 MHz, DMSO-d₆) δ 8.9 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H),7.40 (d, J=9 Hz, 1H), 7.36 (d, J=9.2, H).

B. Preparation of2-(Pyridin-2-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Add tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol) to a 2 Lflask containing a solution of 6-iodo-imidazo[1,2-a]pyridine (6.16 g,25.2 mmol),2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5; 6.07 g, 26.5 mmol), and sodium bicarbonate (4.24 g, 50.5mmol) in 2.5:1 acetonitrile:water (700 mL). Reflux the reaction mixturefor 3 h, cool, concentrate to about one half of the volume, extract intodichloromethane (4×250 ml), and concentrate. Flash chromatography usinga gradient from 100% hexanes to 100% ethyl acetate (10 min, 45 ml/min),followed by isocratic 100% ethyl acetate (2 L), removes most impurities.Elution with ethyl acetate/methanol mixtures followed by tituration inhot ethyl acetate affords the title compound as a white solid 5.46 g,(72%). MS ES⁺ m/e 301.9 (M+1). ¹H-NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H),8.39 (d, J=3.2 Hz, 1H), 7.87 (s, 1H), 7.81-7.76 (m, 2H), 7.51 (d, J=1.2,1H), 7.42 (d, J=9.2 Hz, 1H), 7.26 (m, 1H), 7.05 (dd, J=9.2, 2 Hz, 1H),4.2 (t, J=6.6 Hz, 2H, 2.99 (t, J=6.6 Hz, 2H), 2.59 (m, 1H).

EXAMPLES 15-29 General Suzuki Coupling Method E

Combine either3-bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation 1) or3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation 4, 1.0 eq) with a substituted aryl- or heteroarylboronicacid (1.0 eq-3.0 eq) in the presence of a suitable palladium catalyst,preferably tris(dibenzylidineacetone)dipalladium(0) (0.03 eq-0.10 eq), asuitable ligand, preferably (biphenyl-2-yl)-di-tert-butyl-phosphane(0.06 eq-0.12 eq), and a suitable base, preferably cesium fluoride (2eq-3 eq) in a 4:1 toluene/ethanol mixture in a 10 mL glass tube. Asubstituted aryl- or heteroarylhalide can be combined with the 3-boronicacid analog of the 3-bromo-dihydro-pyrrolo-pyrazole in the same manner.Seal the reaction vessel with a septum and place in the microwavecavity. Use microwave irradiation of 35-150 W to raise the temperatureto 80-130° C. over 90-120 seconds. Hold at the desired temperature for5-30 min. Cool the reaction vessel to room temperature before opening.Add the reaction mixture to SCX resin, elute with dichloromethane,methanol, and then 2.0M ammonia in methanol. Concentrate the methanolicammonia fraction to dryness under reduced pressure. Chromatograph theresidue on silica gel eluting with 20% ethyl acetate/80% hexanes, 40%ethyl acetate/60% hexanes, 60% ethyl acetate/40% hexanes, and 5%methanol/95% ethyl acetate to provide the desired product.

The following compounds were prepared utilizing the General SuzukiCoupling Methods.

Starting Starting Physical Example Product Material A Material B DataComments 15

7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline7-iodo-isoquinoline(Preparation 6)2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 2) MS (ES)m/e 327(M⁺) GeneralSuzukiCouplingMethod E 16

4-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline4-iodo-isoquinoline(Preparation 7)2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5) MS (ES)m/e 313(M⁺) Example15(GeneralSuzukiCouplingMethod E) 17

3-(4-fluoro-benzofuran-7-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole4-fluoro-7-iodo-benzofuran(Preparation 8)2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5) MS (ES)m/e 320(M⁺) Example15(GeneralSuzukiCouplingMethod E) 18

2-methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole5-bromo-2-methylbenzothiazole(available fromTCI)2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5) MS (ES)m/e 333(M⁺) Example15(GeneralSuzukiCouplingMethod E) 19

2-methyl-5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole5-bromo-2-methyl-benzothiazole(available fromTCI)2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 2) MS (ES)m/e 347(M⁺) Example15(GeneralSuzukiCouplingMethod E) 20

3-(4-fluoro-benzofuran-7-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole4-fluoro-7-iodo-benzofuran(Preparation 8)2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 2) MS (ES)m/e 334(M⁺) Example15(GeneralSuzukiCouplingMethod E) 21

7-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline7-iodo-isoquinoline(Preparation 6)2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5) MS (ES)m/e 313(M⁺) Example15(GeneralSuzukiCouplingMethod E) 22

1-methyl-5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indoleN-methylindole-5-boronic acid(available fromFrontier)3-bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation 1)(89 mg,68%). ES⁺m/e 330(M + 1) Example 15(GeneralSuzukCouplingMethod E)23

1-methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1HindoleN-methylindole-5-boronic acid(available fromFrontier3-bromo-2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation4) 315.2(M + 1) Example 15(GeneralSuzukiCouplingMethod E) 24

3-(pyrazin-2-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole2-Iodo-pyrazine(available fromFrontier)2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5) 264.2(M + 1) Example 15(GeneralSuzukiCouplingMethodE) 25

2-(6-methyl-pyridin-2-yl)-3-(pyrazin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole2-iodo-pyrazine(available fromFrontier)2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 2) 278.1(M + 1) Example 15(GeneralSuzukiCouplingMethodE) 26

3-(2,3-dihydro-benzofuran-5-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole5-iodo-2,3-dihydro-benzofuran(available fromFrontier)2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 2) 313.3(M + 1) Example 15(GeneralSuzukiCouplingMethodE) 27

3-(furan-3-yl-2)-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole2-furan-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(availablefromLancaster)3-bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation 1)266(M + 1) Example 15(GeneralSuzukiCouplingMethod E) 28

3-(furan-3-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole2-furan-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(availablefromLancaster)3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation4) 252.2(M + 1) Example 15(GeneralSuzukiCouplingMethod E) 29

2-(6-methyl-pyridin-2-yl)-3-(thiophen-3-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole3-thiopheneboronic acid(available fromMaybridge)3-bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation 1)282.1(M + 1) Example 15(GeneralSuzukiCouplingMethod E)

EXAMPLE 30 Preparation of3-(Benzofuran-5-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Dissolve3-(2,3-dihydro-benzofuran-5-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Example 26; 10 mg, 0.03 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone(14 mg, 0.06 mmol) in anhydrous toluene (4 mL). Heat the mixture for 6hr at 110° C. Evaporate the solvent and purify the crude product byflash chromatography to give target compound as a pale yellow solid (9mg, 91%). MS m/e (315.2, M+1).

EXAMPLE 31 Preparation of6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine

A. Preparation of 6-Bromo-pyrazolo[1,5-a]pyrimidine

Dissolve bromomalonaldehyde (Aldrich; 2.5 g, 16.5 mmol) and3-aminopyrazole (Aldrich; 1.38 g, 16.5 mmol) in glacial acetic acid (25mL) and reflux the resulting mixture under nitrogen for 2 h. Concentrateunder reduced pressure. Dissolve the residue in absolute methanol (150mL), vacuum filter through a pad diatomaceous earth and concentrateunder reduced pressure. Chromatograph on flash silica using a gradientfrom neat hexane to 50% ethyl acetate/50% hexane to obtain 365 mgs (11%)of the subtitled compound as a light yellow solid. High Resolution MassSpectrum: 197.9674 (M+1).

B. Preparation of6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine

To a microwave tube, add 6-bromo-pyrazolo[1,5-a]pyrimidine (0.175 g,0.884 mmol),2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(0.25 g, 1.09 mmol), tetrakis(triphenylphosphine)palladium(0) (31 mg,0.027 mmol), 2M aqueous potassium carbonate (0.5 mL, 1.0 mmol) anddimethylsulfoxide (1.5 mL). Irradiate the reaction in a microwavereactor set at 110° C., 50 Watts, 10 min with external cooling. Dilutethe reaction mixture with diethyl ether (250 mL) and extract the productinto 0.1M aqueous hydrochloric acid (450 mL). Make the aqueous solutionbasic by adding 5M aqueous sodium hydroxide (25 mL) and extract withdichloromethane (300 mL). Filter the organic layer and concentrate underreduced pressure. Recrystallize the resulting solid from ethyl acetate,filter, rinse with ethyl acetate, and dry at 100° C. under vacuum toobtain 70 mg (26%) of the title compound as a tan solid. MS(electrospray, m/z) 302.9 (M+1).

EXAMPLE 32 Preparation of 3-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole

Add bis(1,2-bis(diphenylphosphino)ethane)palladium(0) (Pd(DIPHOS)₂;0.086 g, 0.095 mmol) and tris(dibenzylidene-acetone)dipalladium(0)(Pd₂(dba)₃); 0.088 g, 0.095 mmol) to a degassed solution of3-bromo-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation 4, 0.25 g, 0.95 mmol) in THF (2.5 mL). Purge the reactionmixture with nitrogen for 2 min and stir for 20 min at room temperature.Add 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylboronic acid (158 mg, 0.95mmol) in DMF (1 mL). After stirring the reaction mixture for 10 min, add2M aqueous potassium carbonate solution (1.2 mL). Heat the solution at65° C. for 1 h. Add Pd₂(dba)₃ (0.088 g, 0.095 mmol) twice after 1 h andagain after 2 h. Continue stirring the reaction mixture for 15 h at 65°C. Cool the mixture to room temperature, filter through a Celite® pad,and wash the celite pad with dichloromethane (50 mL) and methanol (50mL). Evaporate the filtrate. Purification of the residue by flashchromatography (SiO₂, 1:3 [88:8:2 chloroform/methanol/concentratedaqueous ammonium hydroxide]/dichloromethane) gives the title compound(69 mg, 22%) as a brown oil.

MS APC+ m/e 334 (M+1). ¹H NMR (CDCl₃) δ 9.09-8.82 (m, 1H), 8.23-8.02 (m,1H), 7.78-7.54 (m, 2H), 7.07-6.94 (m, 1H), 6.87-6.69 (m, 2H), 4.43-4.12(m, 6H), 3.06-2.84 (m, 2H), 2.78-2.63 (m, 2H), 2.30-2.13 (m, 2H).HPLC: >97%, R_(t)=16 min.

Starting Starting Physical Example Product Material A Material B DataComments 33

3-morpholin-4-ylmethyl-6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine6-bromo-3-morpholin-4-ylmethyl-imidazo[1,2-a]pyridine(Preparation 9)2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5) MS ES⁺ m/e401.1(M + 1) Example 32 34

1-morpholin-4-yl-2-[6-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-ethanone2-(6-bromo-imidazo[1,2-a]pyridin-3-yl)-1-morpholin-4-yl-ehtanone(Preparation10)2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5) MS ES⁺ m/e429.2(M + 1) Example 32 35

[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylicacidethyl ester 6-bromo-imidazo[1,2-a]pyridine-3-carboxylicacidethylester. PCT Int.Appl. (2002),WO 0288107Al(Preparation14)2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5) MS ES⁺ m/e373.8(M + 1) Example 32 36

6-[2-(pyridin-2-yl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-imidazo[1,2-a]pyridine6-iodo-imidazo[1,2-a]pyridine(See Example14 a, part A) (Preparation 5a)MS ES⁺ m/e315.8(M + 1) Example 32 37

1-morpholin-4-yl-2-[6-(2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-imidazo[1,2-a]pyridin-2-yl]-ethanone2-(6-bromo-imidazo[1,2-a]pyridin-2-yl)-1-morpholin-4-yl-ethanone(Seepreparation11) 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5a). ES MS(M + 1):277.9 Example 32 38

6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylicacid (2-dimethylamino-ethyl)-amide6-bromo-imidazo[1,2-a]pyridine-3-carboxylicacid(2-dimethylamino-ethyl)-amide(Preparation12)2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5) ES MS(M + 1):416.0 Example 32 39

6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylicacidethyl ester 6-iodo-imidazo[1,2-a]pyridine-2-carboxylicacid ethylester(Preparation13) 3-boronicacid-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation18)ES MS(M + 1):389.9 Example 15(GeneralSuzukiCouplingMethod E) 40

6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylicacidamide Product ofExample 39 ammonia ES MS(M + 1):358.9 Example 44 41

8-fluoro-6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine6-bromo-8-fluoro-imidazo[1,2-a]pyridine(Preparation15)2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5) ES MS(M + 1):319.9 Preparation32(GeneralSuzukiCouplingMethod C) 42

[6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine(6-iodo-imidazo[1,2-a]pyridin-3-yl)-(1,1,3,3-tetramethyl-butyl)-amine(Preparation16)2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5) ES MS(M + 1):429.0 Example15(GeneralSuzukiCouplingMethod E) 43

N-[6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridin-3-yl]-acetamideN-acetyl-N-(6-bromo-imidazo[1,2-a]pyridin-3-yl)-acetamide(Preparation17)2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid(Preparation 5) ES MS(M + 1):358.9 Preparation32(GeneralSuzukiCouplingMethod C)

EXAMPLE 44 Preparation of6-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-imidazo[1,2-a]pyridine-3-carboxylicacid amide

Add 7N ammonia in methanol (10 mL) to a sealed tube containing6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylicacid ethyl ester (Example 35; 0.105 g, 0.28 mmol). Heat at 110° C. for48 h. Flash chromatograph using dichloromethane/methanol mixtures togive the title compound (0.08 g, 82%) as a white solid. MS ES⁺ m/e 344.9(M+1). ¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s, 1H), 8.4-8.37 (m, 1H), 8.28(s, 1H), 7.82-7.77 (m, 3H), 7.59 (d, J=9 Hz, 1H), 7.4 (dd, J=9.0, 2.0Hz, 1H), 7.25 (m, 1H), 4.21 (t, J=7 Hz, 2H), 2.99 (t, J=7, 2H), 2.62(quintet, 2H, 8 Hz).

EXAMPLE 45 Preparation of6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylicAcid (2-Dimethylamino-ethyl)-amide

Add 2M trimethylaluminum in toluene (0.38 mL, 0.38 mmol) to a solutionof N,N-dimethylethylenediamine (0.034 g, 0.38 mmol) in dichloromethane(20 mL). Stir for 20 min and transfer via cannula to a solution of6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylicacid ethyl ester (0.1 g, 0.26 mmol) in dichloromethane (20 mL). Heat at45° C. and stir for 1.5 h. Add saturated aqueous sodium bicarbonate andextract into dichloromethane. Reversed phase chromatography gives thetitled compound (0.067 g, 60%) as a white solid. MS ES⁺ m/e 430.0 (M+1).

EXAMPLE 46 Preparation of6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylicAcid Amide

A. Preparation of6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylicAcid Ethyl Ester

Add tetrakis(triphenylphosphine)palladium(0) (0.53 g, 0.46 mmol) to a 2L flask containing a solution of6-iodo-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (Preparation14; 7.28 g, 23.0 mmol), and sodium bicarbonate (3.87 g, 46.1 mmol) inacetonitrile (350 mL) and water (250 mL). Reflux the reaction mixturefor 3 h. Cool, concentrate to about ⅔ the volume, extract intodichloromethane (4×250 mL), and concentrate. Flash chromatography usinga gradient from 100% hexanes to 100% ethyl acetate (10 min, 45 ml/min),followed by isocratic 9:1 ethyl acetate/methanol gives the subtitledcompound (6.06 g, 67%) as a white solid. TOF MS ES+ exact masscalculated for C₁₀H₉₁N₂O₂ (p+1): m/z=387.1773; Found: 388.1792.

B. Preparation of6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylicAcid Amide

Add formamide (36 mL) to a suspension of sodium hydride (2.04 g, 60%dispersion in mineral oil, 51.1 mmol) and6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylicacid ethyl ester (3.6 g, 9.29 mmol) in DMF (15 mL) over 10 min. Heat at155° C. for 40 min, cool, dilute with ethyl acetate, and carefullydilute with saturated aqueous sodium bicarbonate. Filter anyun-dissolved solid and wash with ethyl acetate. Concentrate theremaining organic layer and adsorb onto a 1:1 mixture of SiO₂ andCelite®. Flash chromatography using ethyl acetate methanol mixturesfollowed by trituration of the combined lots in diethyl ether gives thetitled compound (3.32 g, 99%) as a white solid. TOF MS ES+ exact masscalculated for C₁₀H₉IN₂O₂ (p+1): m/z=359.1620 Found: 359.1617.

EXAMPLE 47 Preparation of7-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine

Combine 7-chloro-imidazo[1,2-a]pyridine (PCT Appl. WO 01/38326 A2; 134mg, 0.88 mmol) with2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5; 369 mg, 0.97 mmol) in the presence oftetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol) and 2Maqueous sodium bicarbonate (1.0 mL) in benzene (2.1 mL) and ethanol (0.3mL). Heat the mixture for 67 h at 100° C. Dilute the reaction withmethylene chloride (10 mL) and water (10 mL). Separate the layers andextract the aqueous layer with methylene chloride (2×10 mL). Combine theorganic layers and dry over sodium sulfate. Filter the solution andevaporate the solvent. Purify the crude product by flash chromatographyusing the appropriate ammonia in methanol/methylene chloride mixture togive the title compound as a tan solid (41 mg, 15%). MS m/e (302.0,M+1). ¹H NMR (CDCl₃) δ 8.57 (m, 1H), 7.96 (dd, J=1, 7 Hz, 1H), 7.6 (m,5H), 7.19 (m, 1H), 6.69 (dd, J=1, 7 Hz, 1H), 4.27 (t, J=8 Hz, 2H),3.08(t, J=7 Hz, 2H), 2.71 (q, J=7 Hz, 2H).

EXAMPLES 48-56 General Suzuki Coupling Method F

Combine the heteroarylboronic acid (1.0 eq) with the heteroaryl halide(1.2 eq) in the presence of[1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) complex withdichloromethane (1:1) (3-5 mol %), a suitable ligand, preferablybiphenyl-2-yl-di-tert-butylphosphane (6-10 mol %), and a suitable base,preferably sodium carbonate (2-3 eq) 4:1 dioxane/ethanol or 1:1DMSO/water in a 10 mL glass tube. Seal the reaction vessel with a septumand place in a microwave reactor. Using microwave radiation raise thetemperature to between 80 and 130° C. over 10 to 30 min. Dilute thereaction mixture with 1:1 chloroform/isopropyl alcohol and wash theresulting solution with saturated sodium chloride solution. Dry theorganic phase over sodium sulfate, filter, and evaporate. Purify theresidue via flash chromatography using gradients of dichloromethane to9% methanol/91% dichloromethane or dichloromethane to 20%tetrahydrofuran/80% dichloromethane to 9% methanol/91% dichloromethaneto provide the desired products.

The following compounds were prepared utilizing the General SuzukiCoupling Methods.

Starting Starting Physical Example Product Material A Material B DataComments 48

3-(4-chloro-phenyl)-6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridinePreparation 183-(4-chloro-phenyl)-6-iodo-imidazo[1,2-a]pyridine(available fromBionet)MS (ES) m/e426.2(M + 1) GeneralSuzukiCouplingMethod F 49

5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazolePreparation 18 5- and 6-iodo-benzoimidazole-1-carboxylic acidtert-butylester(Preparations24/25) MS (ES) m/e316.2(M + 1) Example48(GeneralSuzukiCouplingMethod F) 50

1-methyl-6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazolePreparation 18 6-iodo-1-methyl-1H-benzoimidazole(Preparation 22) MS (ES)m/e330.2(M + 1) Example 48(GeneralSuzukiCouplingMethod F) 51

1-methyl-6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazolePreparation 20 6-iodo-1-methyl-1H-benzoimidazole(Preparation 22) MS (ES)m/e316.2(M + 1) Example 48(GeneralSuzukiCouplingMethod F) 52

1-methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazolePreparation 20 5-iodo-1-methyl-1H-benzoimidazole(Preparation 22) MS (ES)m/e316.2(M + 1) Example 48(GeneralSuzukiCouplingMethod F) 53

1-methyl-5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazolePreparation 18 5-iodo-1-methyl-1H-benzoimidazole(Preparation 22) MS (ES)m/e330.2(M + 1) Example 48(GeneralSuzukiCouplingMethod F) 54

5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazoleand6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazolePreparation 18 5-iodo-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazoleand6-iodo-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole(Preparation23) MS (ES) m/e458.3(M + 1) foreach isomer Example48(GeneralSuzukiCouplingMethod F) 55

5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazoleand6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazolePreparation 205-iodo-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazoleand6-iodo-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole(Preparation23) MS (ES) m/e444.3(M + 1) foreach isomer Preparation33(GeneralSuzukiCouplingMethod Dused replacingacetonitrilewith DMSO) 55a

2-{7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrido[2,3-b]pyrazin-2-yloxy}-ethanolPreparation 18 2-(7-bromoquinoxalin-2-yloxy)ethanol(Preparation 27) MS(ES) m/e388.2 (M + 1) Example 48(GeneralSuzukiCouplingMethod F) 55b

7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-quinoxalin-2-onePreparation 18 2-(7-bromoquinoxalin-2-yloxy)ethanol(Preparation 27) MS(ES) m/e344.1 (M + 1) Example 48(GeneralSuzukiCouplingMethod F) 55c

3-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl][1,5]naphthyridinePreparation 18 2,3-dibromo-[1,5]naphthyridine(available fromBionet) MS(ES) m/e344.1 (M + 1) Example 48(GeneralSuzukiCouplingMethod F)

EXAMPLE 56 Preparation of3-[6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propan-1-ol

Heat a solution of(6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole(Example 54; 368 mg mg, 0.8 mmol) in 4:2:1 aceticacid/tetrahydrofuran/water (20 mL) to 80° C. for 18 h. Remove thesolvent in vacuo and dissolve the residue in excess 3:1chloroform/isopropyl alcohol. Wash the organic layer with saturatedsodium bicarbonate, dry over sodium sulfate, filter, and concentrate invacuo. Purify the residue by column chromatography on silica gel elutingwith dichloromethane to 10% methanol/90% dichloromethane to give thedesired product as a white solid (225 mg, 75%). MS ES⁺ m/e 374.3 (M+1).

Starting Starting Physical Example Product Material A Material B DataComments 57

3-[6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propan-1-olExample 55 Aceticacid/THF/water MS (ES)m/e 360.1(M + 1)

EXAMPLE 57a Preparation of Methanesulfonic Acid3-[6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propylEster

Stir a solution of3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propan-1-ol(Example 56; 257 mg, 0.67 mmol) and methanesulfonyl chloride (200 μl,2.06 mmol) in dry pyridine (5 mL) for 2 h. Remove the pyridine in vacuoand dissolve the residue in excess chloroform. Wash the organic layerwith saturated sodium bicarbonate and dry over sodium sulfate. Filterand concentrate in vacuo to give the product as a white foam (175 mg,55%). MS ES⁺ m/e 452.2 (M+1).

Starting Starting Physical Example Product Material A Material B DataComments 57b

methanesulfonicacid3-[6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propylester Example 37 methanesulfonylchloride/pyridine MS (ES)m/e 438.2(M +1)

EXAMPLE 58 Preparation ofDimethyl-[3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazol-1-yl]propyl]amine

Combine methanesulfonic acid methanesulfonic acid3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propylester (Example 57a; 22 mg, 0.048 mmol) with 2M dimethylamine in THF (2mL). Heat the mixture at 80° C. for 30 min. Cool, evaporate the excessamine, and purify the crude product with FCC to give the title compound(18.5 mg, 95%). MS m/e 401.3 (M+1).

Starting Starting Example Product Material A Material B Physical DataComments 59

diethyl-[3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazol-1-yl]propyl]amineExample 57a diethylamine(availablefrom Aldrich) MS (ES) m/e 429.3(M + 1)60

6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-(3-morpholin-4-yl-propyl)-1H-benzoimidazoleExample 57a morpholine(availablefrom Aldrich) MS (ES) m/e 443.3(M + 1)61

6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-(3-pyrrolidin-1-yl-propyl)-1H-benzoimidazoleExample 57a pyrrolidine(availablefrom Aldrich) MS (ES) m/e 427.3(M + 1)62

6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-(3-piperidin-1-yl-propyl)-1H-benzoimidazoleExample 57a piperidine(availablefrom Aldrich) MS (ES) m/e 441.4(M + 1)

The following compounds were prepared using one of the General SuzukiCoupling Methods.

Starting Starting Example Product Material A Material B Physical DataComments 63

5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole5- and 6-iodo-benzoimidazole-1-carboxylicacidtert-butylester(Preparations24/25) Preparation 5 Mp 121-123° C.MS (ESI)m/e 302(M + 1). ¹H NMR(DMSO-d₆) δ 12.34(br s, 0.5 H), 12.26(br s, 0.5H), 8.42(br s, 1H), 8.13 d,J = 5 Hz, 1H), 7.77(t, J = 8 Hz, 1H), 7.60(d,J = 8 Hz, 1H),7.52 (d, J = 9 Hz,1H), 7.38 (s, 1H),2.26 (dd, J = 7, 5Hz,1H), 7.07 (t, J =6 Hz, 1H), 4.19 (t,J = 7 Hz, 2H), 3.00(dd, J = 8, 7Hz,2H), 2.66-2.56 (m,2H). HPLC: >99%,R_(t) = 10.3 min. TLC(SiO₂): R_(f)0.4(1:1methylenechloride/[80:18:2chloroform/methanol/concentratedaqueousammoniumhydroxide]) Preparation33 (GeneralSuzukiCouplingMethod D) 64

6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline6-bromo-quinoxoline(Landquist, J.Chem. Soc.,1953,2816-2819) Preparation2 Mp 137-139° C.MS (ESI) m/e 328(M + 1). ¹H NMR(300 MHz, CDCl₃)δ 8.78(dd, J = 6, 2Hz, 2H), 8.03 (d, J =2 Hz, 1H), 7.96 (d, J =9 Hz, 1H),7.70(dd, J = 9, 2 Hz,1H), 7.51 (t, J = 8Hz, 1H), 7.32 (d, J =8 Hz, 1H),7.08 (d, J =8 Hz, 1H), 4.31 (t,J = 7 Hz, 2H), 3.13(dd, J = 8, 7 Hz,2H),2.77-2.67 (m,2H), 2.52 (s, 3H).HPLC: >99%, R_(t) =13.7 min.TLC (SiO₂):R_(f) 0.5(1:1methylenechloride/[80:18:2chloroform/methanol/concentratedaqueousammoniumhydroxide]) Preparation30 (GeneralSuzukiCouplingMethod A) 65

2-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline2-bromo-quinoxoline(Kato, Y. et al.TetrahedronLett. 2001, 42,4849-4851)Preparation 5 Mp 162-164° C.MS (ESI) m/e 314(M + 1). ¹H NMR(CDCl₃) δ8.96 (s,1H), 8.53 (d, J = 5Hz, 1H), 8.01 (t, J =7 Hz, 2H), 7.86 (d,J = 8Hz, 1H),7.76-7.69 (m, 3H),7.25 (m, 1H), 4.30 (t,J = 7 Hz, 2H), 3.29(dd,J = 8, 7 Hz, 2H),2.27 (t, J = 8, 7 Hz,2H).HPLC: 97.7%, R_(t) =15.4 min.TLC(SiO₂): R_(f) 0.4(2:1methylenechloride/[80:18:2chloroform/methanol/concentratedaqueousammoniumhydroxide]) Preparation30 (GeneralSuzukiCouplingMethod A) 66

2-[7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalin-2-yloxy]-ethanolPreparation 27 Preparation 2 MS ES⁺ m/e 388.2(M + 1) Example48(GeneralSuzukiCouplingMethod F) 66a

4-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,6]naphthyridinePreparation 20 4-bromo-1,6-naphthiridine(Paudler, W.W.; Kress, T.J. J.Het.Chem. 1965, 2,393-397) MS (APCI) m/e =314 (M + 1)¹H NMR (CDCl₃)δ9.17 (d, J = 1Hz,1H), 9.02 (d, J = 5Hz, 1H), 8.68 (d, J =6 Hz, 1H),8.21(ddd, J = 5, 2, 1 Hz,1H), 7.92 (dd, J = 6,1 Hz, 1H), 7.64-7.54(m,2H), 7.39 (d, J =5 Hz, 1H), 7.07(ddd, J = 6, 4, 1 Hz,1H), 4.37 (t, J =7Hz, 2H), 2.91 (dd, J =8, 6 Hz, 2H),2.78-2.68 (m, 2H).HPLC: 96.2%,R_(t)= 12.3 min. Preparation33 (GeneralSuzukiCouplingMethod D)

EXAMPLE 67 Preparation of6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline

A. Preparation of 6-Iodoisoquinoline

Heat a mixture of 6-bromoisoquinoline (Aldrich; 0.320 g, 1.54 mmol),copper (I) iodide (0.155 g, 0.815 mmol), and potassium iodide (1.27 g,7.96 mmol) in N,N-dimethylformamide (5.0 mL) to 130° C. at 3 h undermicrowave irradiation. Pour the cooled reaction mixture into 4:1dichloromethane/diethyl ether (100 mL) and filter. Wash the filtratewith 5% aqueous sodium bisulfite solution (2×50 mL). Dry the organiclayer over sodium chloride, decant the organic layer, and remove thesolvents under reduced pressure. Dry the residue under vacuum for 18 hto give 0.4 g (100%) of the title compound as a dark red-brown solid.This material is carried on directly to the next step without furtherpurification. MS (electrospray, m/z) 256.1 (M+1).

B. Preparation of6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline

Dissolve 6-iodoisoquinoline (0.085 g, 0.333 mmol) and2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid (Preparation 2; 0.077 g, 0.317 mmol) in dioxane (2.5 mL). Add 5Maqueous potassium carbonate (0.667 mL, 3.33 mmol) followed bytriphenylphosphine (5.2 g, 0.020 mmol) andtris(dibenzylidineacetone)dipalladium (18 mg, 0.020 mmol). Reflux themixture for 2 h and cool to room temperature. Load the reaction mixtureon to a cartridge containing SCX resin (5 g) and wash the resinsequentially with 1 volume dichloromethane, 1 volume methanol, and 1volume methanol containing 2N ammonia. Remove the organic solvents underreduced pressure. Chromatograph on 15 g silica gel eluting with 5%methanol in ethyl acetate to provide 0.053 g (48%) of the title compoundas a tan solid.

MS (electrospray, m/z) 327.4 (M+1).

EXAMPLES 68-70

The following compounds were prepared using one of the General SuzukiCoupling Methods.

Starting Starting Example Product Material A Material B Physical DataComments 68

6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazolePreparation 28 Preparation 5 MS (ESI) m/e 319(M + 1). ¹H NMR(CDCl₃) δ8.95 (s,1H), 8.62 (m, 1H),8.10 (m, 1H), 7.94(s, 1H), 7.62 (m,1H),7.56-7.45 (m,2H), 7.20 (m, 1H),4.32 (t, J = 8 Hz,2H), 3.10 (t, J = 8Hz,2H), 2.82-2.70(m, 2H). HPLC:95.4%, R₁ = 10.32min. TLC (SiO₂):R_(f) 0.25(1:1 [80:18:2chloroform/methanol/concentratdaqueousammoniumhydroxide]/dichloromethane) Preparation33(GeneralSuzukiCouplingMethod D) 69

2-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole2-bromo-benzothiazole(availablefromMaybridge) Preparation 5 MS (ESI) m/e319(M + 1). ¹H NMR(CD₃OD) δ 9.11 (d,J = 6 Hz, 1H), 8.82(d, J = 8 Hz,1H),8.59 (td, J = 8, 1 Hz,1H), 8.28 (d, J = 8Hz, 1H), 8.09-8.01(m, 2H),7.67 (t, J =8 Hz, 1H), 7.54 (t,J = 8 Hz, 1H), 4.42(dd, J = 8, 7 Hz,2H),3.38-3.33 (m,2H), 2.93-2.83 (m,2H). HPLC: 99.5%,R_(t) = 17.38 min.TLC(SiO₂): R_(f) 0.25(10%methanol/dichloromethane) Preparation32(GeneralSuzukiCouplingMethod C) 70

5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazol-2-ylamine5-bromo-benzothiazol-2-ylamine(availablefromOakwood) Preparation 5 MS(ESI) m/e 334(M + 1). ¹H NMR(CDCl₃) δ 8.50(ddd, J = 4, 2, 1 Hz,1H), 7.80(dd, J = 8,2 Hz, 1H), 7.75 (d,J = 2 Hz, 1H), 7.62 (s,1H), 7.36-7.32(m,1H), 7.28 (d, J = 8Hz, 1H), 7.05 (dd,J = 8, 2 Hz, 1H), 4.24(t, J = 7Hz, 2H),3.06 (t, J = 7 Hz,2H), 2.76-2.66 (m,2H). HPLC: 97.1%,R_(t) =11.5 min.TLC (SiO₂): R_(f) 0.1(10%methanol/dichloromethane)Preparation32 (GeneralSuzukiCouplingMethod C)

EXAMPLE 71 Preparation of4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole

A. Preparation of 4-Bromo-indole-1-carboxylic Acid tert-Butyl Ester

Add di-tert-butyl dicarbonate (1.4 g. 6.4 mmol) and sodium hydride (0.15g, 60% dispersion in mineral oil, 3.8 mmol) to a solution of4-bromoindole (0.4 mL, 3.2 mmol) in THF (11 mL) at 0° C. Stir thereaction for 22 h, quench with saturated aqueous ammonium chloride, andextract with methylene chloride. Dry the combined organic extracts withsodium sulfate, filter, and concentrate in vacuo. Purify by flash columnchromatography, utilizing the appropriate mixture of hexanes andmethylene chloride, to provide 0.85 g (90%) of the titled compound as aclear, colorless oil. ¹H NMR (CDCl₃) δ 8.10 (d, J=8 Hz, 1H), 7.63 (d,J=4 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 7.16 (t, J=8 Hz, 1H), 6.64 (d, J=4Hz, 1H), 1.67 (s, 9H). TLC (SiO₂): R_(f)0.3 (9:1 hexanes/methylenechloride).

B. Preparation of4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-indole-1-carboxylicAcid tert-Butyl Ester

The titled intermediate was made via Preparation 33 (General SuzukiCoupling Method D) from 4-bromo-indole-1-carboxylic acid tert-butylester and2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5). MS (ESI) m/e 401 (M+1). TLC (SiO₂): R_(f)0.5 (1:1methylene chloride/[80:18:2 chloroform/methanol/concentrated aqueousammonium hydroxide]).

C. Preparation of4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole

Add trifluoroacetic acid (0.4 mL) to a solution of4-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-indole-1-carboxylicacid tert-butyl ester (34 mg, 0.085 mmol) in methylene chloride (2 mL)at 0° C. Allow the reaction to warm to room temperature slowly over 19h. Dilute the reaction with methylene chloride and methanol. Addconcentrated aqueous ammonium hydroxide (2 mL) and concentrate in vacuo.Purify by flash column chromatography, using the appropriate mixture ofmethylene chloride, chloroform, methanol, and concentrated aqueousammonium hydroxide, to provide 11 mg (8% yield over 2 steps) of thetitle compound as a white solid. MS (APCI) m/e 301 (M+1). ¹H NMR(DMSO-d₆) δ 10.98 (s, 1H), 8.30 (d, J=4 Hz, 1H), 7.65 (td, J=8, 2 Hz,1H), 7.46 (d, J=8 Hz, H), 7.26 (d, J=8 Hz, 1H), 7.17-7.13 (m, 2H), 7.00(t, J=8 Hz, 1H), 6.81 (d, J=7 Hz, 1H), 4.21 (t, J=7 Hz, 2H), 2.85 (dd,J=8, 7 Hz, 2H), 2.64-2.55 (m, 2H). HPLC: >99%, R_(t)=15.1 min. TLC(SiO₂): R_(f)0.2 (1:1 methylene chloride/[80:18:2chloroform/methanol/concentrated aqueous ammonium hydroxide]).

EXAMPLE 72 Preparation of 3-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole

A. Preparation of1-Benzenesulfonyl-3-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-1H-indole

The titled intermediate was made via Preparation 33 (General SuzukiCoupling Method D) from 1-benzene-sulfonyl-3-bromo-1H-indole (Maybridge)and 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronicacid (Preparation 5). MS (ESI) m/e 441 (M+1). TLC (SiO₂): R_(f)0.5 (1:1methylene chloride/[80:18:2 chloroform/methanol/concentrated aqueousammonium hydroxide]).

B. Preparation of 3-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole

Add potassium carbonate (75 mg, 0.55 mmol) to a solution of1-benzenesulfonyl-3-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole(120 mg, 0.27 mmol) in 3:1 methanol/water (1.2 mL). Reflux the reactionmixture for 16 h, cool to room temperature, and add toluene (50 mL).Concentrate in vacuo and purify by flash column chromatography, usingthe appropriate mixture of methylene chloride, chloroform, methanol, andconcentrated aqueous ammonium hydroxide, to provide 6 mg (3% over 2steps) of the title compound as a yellow solid.

MS (APCI) m/e 301 (M+1). ¹H NMR (DMSO-d₆) δ 11.05 (s, 1H), 8.38 (br s,1H), 7.70 (t, J=7 Hz, 1H), 7.57 (d, J=8 Hz, 1H), 7.36 (s, 1H), 7.35 (d,J=8 Hz, 1H), 7.21 (br s, 1H), 7.04-7.00 (m, 2H), 6.82 (dd, J=8, 7 Hz,1H), 4.21 (t, J=7 Hz, 2H), 2.89 (t, J=7 Hz, 2H), 2.73-2.58 (m, 2H).HPLC: >99%, R_(t)=15.7 min. TLC (SiO₂): R_(f)0.4 (1:1 methylenechloride/[80:18:2 chloroform/methanol/concentrated aqueous ammoniumhydroxide]).

EXAMPLES 73-77

The following compounds were prepared using one of the General SuzukiCoupling Methods.

Starting Starting Example Product Material A Material B Physical DataComments 73

3-(2,3-dihydro-benzofuran-5-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole5-iodo-2,3-dihydro-benzofuran(availablefrom FrontierScientificPreparation 5 MS (ES) m/e 304(M + 1) Example48(GeneralSuzukiCouplingMethod F) 74

acetic acid5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzofuran-3-ylesteracetic acid 5-iodo-benzofuran-3-yl ester,(Preparation21a) Preparation 2MS (ES) m/e 374(M + 1) Example 48(GeneralSuzukiCouplingMethod F) 75

3-(5-methoxy-benzofuran-3-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole3-bromo-5-methoxy-benzofuran(Inoue, M. etal. J. Am.Chem. Soc.2001,123,1878-1889) Preparation 2 MS (ES) m/e 346(m + 1) Example48(GeneralSuzukiCouplingMethod F) 76

5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzofuran-2-carboxylicacid 5-bromo-benzofuran-2-carboxylicacid (availablefrom Aldrich)Preparation 2 MS (ES) m/e 360(M + 1) Example48(GeneralSuzukiCouplingMethod F) 77

3-(benzofuran-2-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole3-bromo-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole(Preparation1,Part D) benzofuran-2-boronic acid(availablefromLancaster) MS (ES) m/e316(M + 1) Example 48(GeneralSuzukiCouplingMethod F)

EXAMPLES 78-80 General Suzuki Coupling Method G

To a microwave tube add the substituted boronic acid (1.2 mmol), sodiumbicarbonate (1.2 mmol), the heteroaryl halide (1.0 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.02 mmol). Mix the materialsthoroughly and add 50% aqueous DMSO (2 mL). Irradiate the reactionmixture in a microwave reactor set at 50 W, 90° C. for 10 min withexternal cooling. Dilute the reaction mixture with methanol (25 mL) andload the mixture onto a SCX column. Rinse the column with absolutemethanol and elute with 2M ammonia in methanol. Combine fractions,condentrate under reduced pressure and chromatograph on silica gel usinga gradient of neat ethyl acetate to 40% methanol/60% ethyl acetate.Further purify the isolated product via reverse-phase high-performancechromatography if needed.

The following compounds were prepared utilizing the General SuzukiCoupling Methods.

Starting Starting Example Product Material A Material B Physical DataComments 78

5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine5-iodo-pyrazolo[1,5-a]pyrimidine(Preparation29) Preparation 5 TOF MS ES⁺exactmass calculated forC₁₇H₁₅N₆ (p + H):m/z = 303.1358;Found:303.1354,¹H NMR (400 MHz,DMSO-d₆) δ 8.83(d, J=8 Hz, 1H),8.51 (m, 1H),8.10(m, 1H), 7.87 (m,1H), 7.78 (m, 1H),7.36 (m, 1H), 6.89(d, J=8 Hz,1H),6.52 (m, 1H), 4.20(t, J=7 Hz, 2H), 3.13(t, J=7 Hz, 2H), 2.62(m, 2H).(GeneralSuzukiCouplingMethod G) 79

5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine5-iodo-pyrazolo[1,5-a]pyrimidine(Preparation29) Preparation 2 TOF MS ES⁺exactmass calculated forC₁₈H₁₇N₆ (p + H):m/z = 317.1515;Found:317.1519.¹NMR (400 MHz,DMSO-d₆) δ 8.85(d, J=8 Hz, 1H),8.10 (m, 1H),7.74(m, 1H), 7.58 (d,J=8 Hz 1H), 7.22 (d,J=8 Hz, 1H), 7.01(d, J=8 Hz,1H),6.53 (m, 1H), 4.19(t, J=7 Hz, 2H), 3.13(t, J=7 Hz, 2H), 2.61(m, 2H),2.38 (s,3H). Example 78(GeneralSuzukiCouplingMethod G) 80

5-[2-(pyridin-2-yl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-pyrazolo[1,5-a]pyrimidine5-iodo-pyrazolo[1,5-a]pyrimidine(Preparation29)2-(pyridin-2-yl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridine-3-boronicacidPreparation 5a TOF MS ES⁺ exactmass calculated forC₁₈H₁₇N₆ (p +H):m/z = 317.1515;Found: 317.1517,¹H NMR (400 MHz,DMSO-d₆) δ 8.81(d, J=8Hz, 1H),8.44 (m, 1H), 8.12(m, 1H), 7.85 (m,1H), 7.79 (m, 1H),7.32 (m,1H), 6.66(d, J=8 Hz, 1H),6.58 (m, 1H), 4.19(t, J=6 Hz, 2H), 2.99(t, J=6Hz, 2H), 2.03(m, 2H), 1.83 (m,2H). Example78(GeneralSuzukiCouplingMethod G)

EXAMPLE 80a Preparation of8-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-[1,6]naphthyridine

Add 8-bromo-[1,6]naphthyridine (Spec; 32 mg, 0.152 mmol),2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5; 35 mg, 0.153 mmol), and potasium phosphate (97 mg, 0.458mmol) to DMF (1 mL) and water (0.5 mL). De-gas the solution with argonand add tetrakis(triphenylphosphine)palladium(0) (88 mg, 0.076 mol).Heat the mixture at 60° C. for 18 h under an argon atmosphere. Cool themixture to room temperature and dilute with water. Filter the mixture,and separate the filtrate. Extract the aqueous layer withdichloromethane. Dry the combined organic layers over sodium sulfate,filter, and concentrate. Purify the crude residue by columnchromatography (12 g Redisep column, gradient dichloromethane throughCMA over 40 min, 20 mL/min) to provide the title compound (31 mg, 64%)as an off white solid. Mp 180-184° C. MS (APCI) m/e=314 (M+1). ¹H NMR(CDCl₃) δ 8.88 (dd, J=1.6, 4.2 Hz, 1H), 8.60 (d, J=4.7 Hz, 1H), 8.28 (d,J=8.5 Hz, 1H), 8.19 (d, J=8.9 Hz, 1H), 7.73-7.68 (m, 3H), 7.58 (dd,J=4.2, 8.5 Hz, 2H), 4.30 (t, J=7 Hz, 2H), 3.30 (t, J=7 Hz, 2H), 2.73 (p,J=7 Hz, 2H). HPLC: >99%, R_(t)=7.1 min.

EXAMPLE 81 Preparation of 3-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-pyrazolo[1,5-a]pyrimidine

Weigh into a round bottom flask 3-bromopyrazolo[1,5-a]pyrimidine (Lynchet al. Can. J. Chem. 1975, 53, 119-122; 0.095 g, 0.48 mmol),2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid(Preparation 5; 0.10 g, 0.44 mmol), triphenylphosphine (Aldrich; 0.007g, 0.027 mmol) and tris(dibenzylideneacetone)dipalladium(0) (Aldrich;0.015 g, 0.016 mmol). Add p-dioxane (6 ml) and 2.0M aqueous potassiumcarbonate (2 mL). Stir and reflux under nitrogen for 6 h. Dilute withethyl acetate, separate the organic layer, concentrate under reducedpressure, and chromatograph on flash silica using neat acetonitrile.Purify on a preparative reverse phase C-18 high-performancechromatography column using a gradient from 5% to 100% acetonitrile in0.03% aqueous hydrochloric acid. Concentrate the pure fractions underreduced pressure, dissolve the residue in distilled water, and makebasic by adding 1.0M aqueous sodium hydroxide. Extract withdichloromethane, dry the organic layer over anhydrous sodium sulfate,filter, and concentrate under reduced pressure to obtain 6 mg (4.5%) ofthe title compound as a yellow solid. TOF MS ES⁺ exact mass calculatedfor C₁₇H₁₅N₆ (M+1): m/z=303.1358; Found: 303.1371. ¹H NMR (400 MHz,CDCl₃) δ 8.66 (d, J=2 Hz, 1H), 8.64 (d, J=2 Hz, 1H), 8.41 (dd, J=4, 2Hz, 1H), 8.31 (s, 1H), 7.70 (m, 2H), 7.21 (m, 1H), 6.79 (dd, J=7, 4 Hz,1H), 4.30 (t, J=7 Hz, 2H), 3.10 (t, J=8 Hz, 2H), 2.68 (m, 2H).

EXAMPLE 82

The following compound was prepared using General Suzuki Coupling MethodC (Preparation 32).

Starting Starting Example Product Material A Material B Physical DataComments 82

2-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,5]naphthyridine2-bromo-1,5-naphthiridine(Czuba, Z.Recueil 1963,82, 988-996).Preparation 5 Mp 189-191° C.MS (ESI) m/e 314(M + 1). ¹H NMR(CDCl₃) δ8.89 (dd,J = 4, 1 Hz, 1H),8.62 (br s, 1H), 8.28(d, J = 8 Hz, 1H),8.18(d, J = 9 Hz,1H), 7.75-7.56 (m,4H), 7.25 (m, 1H),4.29 (dd, J = 8, 7Hz,2H), 3.30 (dd,J = 8, 7 Hz, 2H),2.78-2.71 (m, 2H).HPLC: 98.0%, R_(t)=14.4 min.TLC (SiO₂): R_(f) 0.3(2:1methylenechloride/[80:18:2chloroform/methanol/concentratedaqueousammoniumhydroxide]). Preparation32 (GeneralSuzukiCouplingMethod C)

EXAMPLE 832-Chloro-7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline

Dissolve7-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-quinoxalin-2-one(Example 55b; 200 mg, 0.6 mmol) in phosphorus oxychloride (20 mL).Reflux the solution for 30 min. Evaporate in vacuo. Dissolve the residuein 3:1 chloroform/isopropyl alcohol (100 mL) and wash the solution with5% aqueous ammonia solution, brine and water. Dry the organic phase oversodium sulfate. Filter and evaporate the solvents in vacuo to give thetarget product as a yellow solid 180 mg (86%). MS (electrospray, m/z)362.2 (M+1).

EXAMPLE 84Dimethyl-(2-{7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalin-2-yloxy}-ethyl)-amine

Combine of 2-dimethylaminoethanol (180 mg, 2 mmol) with of sodiumhydride (48 mg, 2 mmol) in dry DMF (5 mL) at 0-5° C. Stir for 10 min,add2-chloro-7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline(Example 83; 60 mg, 0.17 mmol) in DMF (5 mL). Stir the reaction mixturefor an additional 1 h. Dilute the mixture with dichloromethane. Wash theorganic solution with brine, dry over sodium sulfate, filter andevaporate. Purify the crude product by column chromatography on silicagel to give target compound 35 mg (51%) as white solid. MS(electrospray, m/z) 414.2 (M+1). ¹H NMR (CD₂Cl₂) δ 8.4 (s, 1H), 7.85 (d,8.8 Hz, 1H), 7.81 (d, 1.6 Hz, 1H), 7.56 (t, 8.0 Hz, 1H), 7.51 (dd, 8.8Hz, 1.6 Hz, 1H), 7.43 (d, 8.0 Hz, 1H), 7.09 (d, 8.0 Hz, 1H), 4.59 (t, 6Hz, 2H), 4.27 (t, 7.2 Hz, 2H), 3.13 (t, 7.2 Hz, 2H), 2.80 (t, 6 Hz, 2H),2.73 (m, 2H), 2.42 (s, 3H), 2.34 (s, 3H).

Starting Starting Example Product Material A Material B Physical DataComments 85

dimethyl-(2-{7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalin-2-yloxy}-ethyl)-amine2-chloro-7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline2-dimethylaminopropanol MS (electrospray,m/z) 429.2 (M + 1).

EXAMPLE 867-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline-2-carboxylicacid amide

Reflux7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-quinoxalin-2-one(Example 55b; 20 mg, 0.055 mmol,) in POCl₃ overnight. After removingPOCl₃, treat the residue with Zn(CN)₂ (11.6 mg, 0.11 mmol) and Pd(PPh₃)₄(3 mg, 0.003 mmol) in DMF (1 mL) at 100° C. for 20 min in microwave.Cool the solution to room temperature, dilute with chloroform/isopropylalcohol and wash with brine. Dry the solution over sodium sulfate,filter, and evaporate the solvents to give a viscous mixture. Purify thecrude product by column chromatography eluting with a gradient fromdichloromethane to 10% methanol in dichloromethane to give the desiredcompound 12 mg (59%). MS (electrospray, m/z) 371.2 (M+1).

The compounds disclosed herein were tested by the following protocolsfor TGF-β inhibition, as described below in the protocol description.

TGF-β Receptor I Purification and In Vitro Kinase Reactions

For TGF-β Type I (RIT204D) Receptors

The 6×-HIS tagged cytoplasmic kinase domain of each receptor wasexpressed and purified from Sf9 insect cell lysates as briefly describedbelow: Cell pellets after 48-72 h of infection were lysed in lysisbuffer (LB: 50 mM Tris pH 7.5, 150 mM NaCl, 50 mM NaF, 0.5% NP40 withfreshly added 20 mM β-mercaptoethanol, 10 mM imidazole, 1 mM PMSF,1×EDTA-free Complete Protease Inhibitor (Boehringer Mannheim). Celllysates were clarified by centrifugation and 0.45 uM filtered prior topurification by Ni/NTA affinity chromatography (Qiagen).

Chromatography Protocol

Equilibrate with 10 CV of LB, load sample, wash with 10 CV RIPA buffer(50 mM Tris pH 7.5, 150 mM NaCl, 1% NP40, 1 mM EDTA, 0.25% sodiumdeoxycholate, added fresh 20 mM β-mercaptoethanol, 1 mM PMSF), wash with10 CV LB, wash with 10 CV 1×KB (50 mM Tris pH 7.5, 150 mM NaCl, 4 mMMgCl₂, 1 mM NaF, 2 mM β-mercaptoethanol), elute with a linear gradientof 1× KB containing 200 mM Imidazole. Both enzymes were approximately90% pure and had autophosphorylation activity. Reactions: 170-200 nMenzyme in 1×KB, compound dilution series in 1×KB/16% DMSO (20 μM to 1 nMfinal concentration with 4% DMSO final concentration), reactions startedby adding ATP mix (4 uM ATP/1 uCi ³³P-γ-ATP final concentrations) in1×KB.

Reactions were incubated at 30° C. for 1 h. Reactions were stopped andquantitated using standard TCA/BSA precipitation onto Millipore FB glassfiber filter plates and by liquid scintillation counting on a MicroBetaJET.

Representative compounds of the current invention which inhibit theTGF-β Type I (RIT204D) receptor kinase domain with IC₅₀ values <20 μMare listed in Table I.

TABLE I COMPOUND NAME a.3-(2-Phenyl-oxazol-5-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole b.4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzo[2,1,3]thiadiazole c.5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]benzo[2,1,3]thiadiazole d.6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalinee. 2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-imidazo[4,5-c]pyridine f.2-(Pyridin-2-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole g.7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline h.3-(4-Fluoro-benzofuran-7-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole i.2-Methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole j.2-Methyl-5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole k.3-(4-Fluoro-benzofuran-7-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole l.7-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinolinem.1-Methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole n.1-Methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1Hindole o.3-(Pyrazin-2-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolep.2-(6-Methyl-pyridin-2-yl)-(3-pyrazin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole q.3-(2,3-Dihydro-benzofuran-5-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole r.3-(Furan-3-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole s.2-(6-Methyl-pyridin-2-yl)-3-(thiophen-3-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole t.3-(Benzofuran-5-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole u.6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine v.3-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole w.3-Morpholin-4-ylmethyl-6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine x.1-Morpholin-4-yl-2-[6-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-ethanone y.6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic acid z.6-[2-(Pyridin-2-yl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-imidazo[1,2-a]pyridine aa.1-Morpholin-4-yl-2-[6-(2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-imidazo[1,2-a]pyridin-2-yl]-ethanone bb.6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic acid (2-dimethylamino-ethyl)-amide cc.6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester dd.6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylic acid amide ee.8-Fluoro-6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine ff.[6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine gg.-[6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridin-3-yl]-acetamide hh.6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic Acid Amide ii.6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylic Acid (2-Dimethylamino-ethyl)-amidejj.6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic Acid Amide kk.7-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine ll.3-(4-Chloro-phenyl)-6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine mm.5-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole nn.1-Methyl-6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole oo.1-Methyl-6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole pp.1-Methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole qq.1-Methyl-5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole rr.5-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole ss.6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole tt.5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole uu.6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole vv.2-{7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrido[2,3-b]pyrazin-2-yloxy}-ethanol ww.7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-quinoxalin-2-one xx.3-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl][1,5]naphthyridine yy.3-[6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propan-1-ol zz.3-[6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propan-1-ol aaa. Methanesulfonic Acid3-[6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propyl Ester bbb.Methanesulfonic acid 3-[6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propyl ester ccc.Dimethyl-[3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazol-1-yl]propyl]amine ddd.Diethyl-[3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazol-1-yl]propyl]amine eee.6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-(3-morpholin-4-yl-propyl)-1H-benzoimidazole fff.6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-(3-pyrrolidin-1-yl-propyl)-1H-benzoimidazole ggg.6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-(3-piperidin-1-yl-propyl)-1H-benzoimidazole hhh.5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole iii.6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline jjj.2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalinekkk.2-[7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalin-2-yloxy]-ethanol lll.4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,6]naphthyridine mmm.6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline nnn.6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazoleooo.5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazol-2-ylamine ppp.4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indoleqqq.3-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indolerrr. 3-(2,3-Dihydro-benzofuran-5-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole sss. Acetic acid5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzofuran-3-yl ester ttt.3-(5-Methoxy-benzofuran-3-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole uuu.5-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzofuran-2-carboxylic acid vvv.3-(Benzofuran-2-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole www.5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine xxx.5-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine yyy.5-[2-(Pyridin-2-yl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-pyrazolo[1,5-a]pyrimidine zzz.8-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,6]naphthyridine aaaa.3-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-pyrazolo[1,5-a]pyrimidine bbbb.2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,5]naphthyridine cccc.Dimethyl-(2-{7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalin-2-yloxy}-ethyl)-amine dddd.Dimethyl-(2-{7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalin-2-yloxy}-propyl)-amine eeee.7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline-2-carboxylic acid amide

Conditions “characterized by enhanced TGF-β activity” include thosewherein TGF-β synthesis is stimulated so that TGF-β is present atincreased levels or wherein TGF-β latent protein is undesirablyactivated or converted to active TGF-β protein or wherein TGF-βreceptors are upregulated or wherein the TGF-β protein shows enhancedbinding to cells or extracellular matrix in the location of the disease.Thus, in either case “enhanced activity” refers to any condition whereinthe biological activity of TGF-β is undesirably high, regardless of thecause.

A number of diseases have been associated with TGF-β1 over production.Inhibitors of TGF-β intracellular signaling pathway are usefultreatments for fibroproliferative diseases. Specifically,fibroproliferative diseases include kidney disorders associated withunregulated TGF-β activity and excessive fibrosis includingglomerulonephritis (GN), such as mesangial proliferative GN, immune GN,and crescentic GN. Other renal conditions include diabetic nepbropathy,renal interstitial fibrosis, renal fibrosis in transplant patientsreceiving cyclosporin, and HIV-associated nephropathy. Collagen vasculardisorders include progressive systemic sclerosis, polymyositis,scleroderma, dermatomyositis, eosinophilic fascitis, morphea, or thoseassociated with the occurrence of Raynaud's syndrome. Lung fibrosesresulting from excessive TGF-β activity include adult respiratorydistress syndrome, idiopathic pulmonary fibrosis, and interstitialpulmonary fibrosis often associated with autoimmune disorders, such assystemic lupus erythematosus and scleroderma, chemical contact, orallergies. Another autoimmune disorder associated withfibroproliferative characteristics is rheumatoid arthritis.

Eye diseases associated with a fibroproliferative condition includeretinal reattachment surgery accompanying proliferativevitreoretinopathy, cataract extraction with intraocular lensimplantation, and post glaucoma drainage surgery are associated withTGF-β overproduction.

Fibrotic diseases associated with TGF-β1 overproduction can be dividedinto chronic conditions such as fibrosis of the kidney, lung and liverand more acute conditions such as dermal scarring and restenosis(Chamberlain, J. Cardiovascular Drug Reviews, 19(4):329-344). Synthesisand secretion of TGF-β1 by tumor cells can also lead to immunesuppression such as seen in patients with aggressive brain or breasttumors (Arteaga, et al. (1993) J. Clin. Invest. 92:2569-2576). Thecourse of Leishmanial infection in mice is drastically altered by TGF-β1(Barral-Netto, et al. (1992) Science 257:545-547). TGF-β1 exacerbatedthe disease, whereas TGF-β1 antibodies halted the progression of thedisease in genetically susceptible mice. Genetically resistant micebecame susceptible to Leishmanial infection upon administration ofTGF-β1.

The profound effects of TGF-β1 on extracellular matrix deposition havebeen reviewed (Rocco and Ziyadeh (1991) in Contemporary Issues inNephrology v.23, Hormones, autocoids and the kidney. ed. Jay Stein,Churchill Livingston, N.Y. pp. 391-410; Roberts, et al. (1988) Rec.Prog. Hormone Res. 44:157-197) and include the stimulation of thesynthesis and the inhibition of degradation of extracellular matrixcomponents. Since the structure and filtration properties of theglomeralus are largely determined by the extracellular matrixcomposition of the mesangium and glomerular membrane, it is notsurprising that TGF-β1 has profound effects on the kidney. Theaccumulation of mesangial matrix in proliferative glomeralonephritis(Border, et al. (1990) Kidney Int. 37:689-695) and diabetic nephropathy(Mauer, et al. (1984) J. Clin. Invest. 74:1143-1155) are clear anddominant pathological features of the diseases. TGF-β1 levels areelevated in human diabetic glomerulosclerosis (advanced neuropathy)(Yamamoto, et al. (1993) Proc. Natl. Acad. Sci. 90:1814-1818). TGF-β1 isan important mediator in the genesis of renal fibrosis in a number ofanimal models (Phan, et al. (1990) Kidney Int. 37:426; Okuda, et al.(1990) J. Clin. Invest. 86:453). Suppression of experimentally inducedglomerulonephritis in rats has been demonstrated by antiserum againstTGF-β1 (Border, et al. (1990) Nature 346:371) and by an extracellularmatrix protein, decorin, which can bind TGF-β1 (Border, et al. (1992)Nature 360:361-363).

Too much TGF-β1 leads to dermal scar-tissue formation. NeutralizingTGF-β1 antibodies injected into the margins of healing wounds in ratshave been shown to inhibit scarring without interfering with the rate ofwound healing or the tensile strength of the wound (Shah, et al. (1992)Lancet 339:213-214). At the same time there was reduced angiogenesis,reduced number of macrophages and monocytes in the wound, and a reducedamount of disorganized collagen fiber deposition in the scar tissue.

TGF-β1 may be a factor in the progressive thickening of the arterialwall which results from the proliferation of smooth muscle cells anddeposition of extracellular matrix in the artery after balloonangioplasty. The diameter of the restenosed artery may be reduced 90% bythis thickening, and since most of the reduction in diameter is due toextracellular matrix rather than smooth muscle cell bodies, it may bepossible to open these vessels to 50% simply by reducing extensiveextracellular matrix deposition. In uninjured pig arteries transfectedin vivo with a TGF-β1 gene, TGF-β1 gene expression was associated withboth extracellular matrix synthesis and hyperplasia (Nabel, et al.(1993) Proc. Natl. Acad. Sci. USA 90:10759-10763). The TGF-β1 inducedhyperplasia was not as extensive as that induced with PDGF-BB, but theextracellular matrix was more extensive with TGF-β1 transfectants. Noextracellular matrix deposition was associated with FGF-1 (a secretedform of FGF) induced hyperplasia in this gene transfer pig model (Nabel(1993) Nature 362:844-846).

There are several types of cancer where TGF-β1 produced by the tumor maybe deleterious. MATLyLu rat prostate cancer cells (Steiner and Barrack(1992) Mol. Endocrinol 6:15-25) and MCF-7 human breast cancer cells(Arteaga, et al. (1993) Cell Growth and Differ. 4:193-201) became moretumorigenic and metastatic after transfection with a vector expressingthe mouse TGF-β1. TGF-β1 has been associated with angiogenesis,metastasis and poor prognosis in human prostate and advanced gastriccancer (Wikstrom, P., et al. (1998) Prostate 37: 19-29; Saito, H. et al.(1999) Cancer 86: 1455-1462). In breast cancer, poor prognosis isassociated with elevated TGF-β (Dickson, et al. (1987) Proc. Natl. Acad.Sci. USA 84:837-841; Kasid, et al. (1987) Cancer Res. 47:5733-5738;Daly, et al. (1990) J. Cell Biochem. 43:199-211; Barrett-Lee, et al.(1990) Br. J. Cancer 61:612-617; King, et al. (1989) J. Steroid Biochem.34:133-138; Welch, et al. (1990) Proc. Natl. Acad. Sci. USA87:7678-7682; Walker, et al. (1992) Eur. J. Cancer 238:641-644) andinduction of TGF-β1 by tamoxifen treatment (Butta, et al. (1992) CancerRes. 52:4261-4264) has been associated with failure of tamoxifentreatment for breast cancer (Thompson, et al. (1991) Br. J. Cancer63:609-614). Anti TGF-β1 antibodies inhibit the growth of MDA-231 humanbreast cancer cells in athymic mice (Arteaga, et al. (1993) J. Clin.Invest. 92:2569-2576), a treatment which is correlated with an increasein spleen natural killer cell activity. CHO cells transfected withlatent TGF-β1 also showed decreased NK activity and increased tumorgrowth in nude mice (Wallick, et al. (1990) J. Exp. Med. 172:1777-1784).Thus, TGF-β secreted by breast tumors may cause an endocrine immunesuppression. High plasma concentrations of TGF-β1 have been shown toindicate poor prognosis for advanced breast cancer patients (Anscher, etal. (1993) N. Engl. J. Med. 328:1592-1598). Patients with highcirculating TGF-β before high dose chemotherapy and autologous bonemarrow transplantation are at high risk for hepatic veno-occlusivedisease (15-50% of all patients with a mortality rate up to 50%) andidiopathic interstitial pneumonitis (40-60% of all patients). Theimplication of these findings is 1) that elevated plasma levels ofTGF-β1 can be used to identify at risk patients and 2) that reduction ofTGF-β1 could decrease the morbidity and mortality of these commontreatments for breast cancer patients.

Many malignant cells secrete transforming growth factory (TGF-β), apotent immunosuppressant, suggesting that TGF-β production may representa significant tumor escape mechanism from host immunosurveillance.Establishment of a leukocyte sub-population with disrupted TGF-βsignaling in the tumor-bearing host offers a potential means forimmunotherapy of cancer. A transgenic animal model with disrupted TGF-βsignaling in T cells is capable of eradicating a normally lethal TGF-βoverexpressing lymphoma tumor, EL4 (Gorelik and Flavell, (2001) NatureMedicine 7(10): 1118-1122). Down regulation of TGF-β secretion in tumorcells results in restoration of immunogenicity in the host, while T-cellinsensitivity to TGF-β results in accelerated differentiation andautoimmunity, elements of which may be required in order to combatself-antigen-expressing tumors in a tolerized host. Theimmunosuppressive effects of TGF-β have also been implicated in asubpopulation of HIV patients with lower than predicted immune responsebased on their CD4/CD8 T cell counts (Garba, et al. J. Immunology (2002)168: 2247-2254). A TGF-β neutralizing antibody was capable of reversingthe effect in culture, indicating that TGF-β signaling inhibitors mayhave utility in reversing the immune suppression present in this subsetof HIV patients.

During the earliest stages of carcinogenesis, TGF-β1 can act as a potenttumor suppressor and may mediate the actions of some chemopreventiveagents. However, at some point during the development and progression ofmalignant neoplasms, tumor cells appear to escape from TGF-β-dependentgrowth inhibition in parallel with the appearance of bioactive TGF-β inthe microenvironment. The dual tumor suppression/tumor promotion rolesof TGF-β have been most clearly elucidated in a transgenic systemoverexpressing TGF-β in keratinocytes. While the transgenics were moreresisitant to formation of benign skin lesions, the rate of metastaticconversion in the transgenics was dramatically increased (Cui, et al(1996) Cell 86(4):531-42). The production of TGF-β1 by malignant cellsin primary tumors appears to increase with advancing stages of tumorprogression. Studies in many of the major epithelial cancers suggestthat the increased production of TGF-β by human cancers occurs as arelatively late event during tumor progression. Further, thistumor-associated TGF-β provides the tumor cells with a selectiveadvantage and promotes tumor progression. The effects of TGF-β oncell/cell and cell/stroma interactions result in a greater propensityfor invasion and metastasis. Tumor-associated TGF-β may allow tumorcells to escape from immune surveillance since it is a potent inhibitorof the clonal expansion of activated lymphocytes. TGF-β has also beenshown to inhibit the production of angiostatin. Cancer therapeuticmodalities such as radiation therapy and chemotherapy induce theproduction of activated TGF-β in the tumor, thereby selecting outgrowthof malignant cells that are resistant to TGF-β growth inhibitoryeffects. Thus, these anticancer treatments increase the risk and hastenthe development of tumors with enhanced growth and invasiveness. In thissituation, agents targeting TGF-β-mediated signal transduction might bea very effective therapeutic strategy. The resistance of tumor cells toTGF-β has been shown to negate much of the cytotoxic effects ofradiation therapy and chemotherapy and the treatment-dependentactivation of TGF-β in the stroma may even be detrimental as it can makethe microenvironment more conducive to tumor progression and contributesto tissue damage leading to fibrosis. The development of a TGF-β signaltransduction inhibitors is likely to benefit the treatment of progressedcancer alone and in combination with other therapies.

The compounds are useful for the treatment of cancer and other diseasestates influenced by TGF-β by inhibiting TGF-β in a patient in needthereof by administering said compound(s) to said patient. TGF-β wouldalso be useful against atherosclerosis (T. A. McCaffrey: TGF-βs andTGF-β Receptors in Atherosclerosis: Cytokine and Growth Factor Reviews2000, 11, 103-114) and Alzeheimer's (Masliah, E.; Ho, G.; Wyss-Coray,T.: Functional Role of TGF-β in Alzheimer's Disease MicrovascularInjury: Lessons from Trangenic Mice: Neurochemistry International 2001,39, 393-400) diseases.

Pharmaceutical Compositions

The compositions of the present invention are therapeutically effectiveamounts of the TGF-β antagonists, noted above. The composition may beformulated with common excipients, diluents or carriers, and compressedinto tablets, or formulated elixirs or solutions for convenient oraladministration or administered by intramuscular intravenous routes. Thecompounds can be administered transdermally and maybe formulated assustained release dosage forms and the like.

The method of treating a human patient according to the presentinvention includes administration of the TGF-β antagonists. The TGF-βantagonists are formulated into formulations which may be administeredby the oral and rectal routes, topically, parenterally, e.g., byinjection and by continuous or discontinuous intra-arterial infusion, inthe form of, for example, tablets, lozenges, sublingual tablets,sachets, cachets, elixirs, gels, suspensions, aerosols, ointments, forexample, containing from 1 to 10% by weight of the active compound in asuitable base, soft and hard gelatin capsules, suppositories, injectablesolutions and suspensions in physiologically acceptable media, andsterile packaged powders adsorbed onto a support material for makinginjectable solutions. Advantageously for this purpose, compositions maybe provided in dosage unit form, preferably each dosage unit containingfrom about 5 to about 500 mg (from about 5 to 50 mg in the case ofparenteral or inhalation administration, and from about 25 to 500 mg inthe case of oral or rectal administration) the compounds. Dosages fromabout 0.5 to about 300 mg/kg per day, preferably 0.5 to 20 mg/kg, ofactive ingredient may be administered although it will, of course,readily be understood that the amount of the compound actually to beadministered will be determined by a physician, in the light of all therelevant circumstances including the condition to be treated, the choiceof compound to be administered and the choice of route of administrationand therefore the above preferred dosage range is not intended to limitthe scope of the present invention in any way.

The formulations useful for separate administration of the TGF-βantagonists will normally consist of at least one compound selected fromthe compounds specified herein mixed with a carrier, or diluted by acarrier, or enclosed or encapsulated by an ingestible carrier in theform of a capsule, sachet, cachet, paper or other container or by adisposable container such as an ampoule. A carrier or diluent may be asolid, semi-solid or liquid material which serves as a vehicle,excipient or medium for the active therapeutic substance. Some examplesof the diluents or carrier which may be employed in the pharmaceuticalcompositions of the present invention are lactose, dextrose, sucrose,sorbitol, mannitol, propylene glycol, liquid paraffin, white softparaffin, kaolin, fumed silicon dioxide, microcrystalline cellulose,calcium silicate, silica, polyvinylpyrrolidone, cetostearyl alcohol,starch, modified starches, gum acacia, calcium phosphate, cocoa butter,ethoxylated esters, oil of theobroma, arachis oil, alginates,tragacanth, gelatin, syrup, methyl cellulose, polyoxyethylene sorbitanmonolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitantrioleate, sorbitan sesquioleate and oleyl alcohol and propellants suchas trichloromonofluoromethane, dichlorodifluoromethane anddichlorotetrafluoroethane. In the case of tablets, a lubricant may beincorporated to prevent sticking and binding of the powdered ingredientsin the dies and on the punch of the tableting machine. For such purposethere may be employed for instance aluminum, magnesium or calciumstearates, talc or mineral oil.

Preferred pharmaceutical forms of the present invention are capsules,tablets, suppositories, injectable solutions, creams and ointments.Especially preferred are formulations for inhalation application, suchas an aerosol, for injection, and for oral ingestion.

1. A compound selected from the group of: a)2-(Pyridin-2-yl)-3-(thiophen-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;b)5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole;c)3-(2-Phenyl-oxazol-5-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;d) 4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzo[2,1,3]thiadiazole; e)5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]benzo[2,1,3]thiadiazole;f)6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline;g)5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline;h) 2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-imidazo[4,5-b]pyridine; i)2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-imidazo[4,5-c]pyridine;j)2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole;k)2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-oxazolo[4,5-b]pyridine;l)2-Dimethylamino-N-[6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,8]naphthyridin-2-yl]-acetamide;m)4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,8]naphthyridine;n)2-(Pyridin-2-yl)-3-(imidazo[1,2-a]pyridin-6-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;o)7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline;p)4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline;q)3-(4-Fluoro-benzofuran-7-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;r)2-Methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole;s)2-Methyl-5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole;t)3-(4-Fluoro-benzofuran-7-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;u)7-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline;v)1-Methyl-5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole;w)1-Methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1Hindole; x)3-(Pyrazin-2-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;y)2-(6-Methyl-pyridin-2-yl)-3-(pyrazin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;z)3-(2,3-Dihydro-benzofuran-5-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;aa)3-(Furan-3-yl-2)-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;bb)3-(Furan-3-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;cc)2-(6-Methyl-pyridin-2-yl)-3-(thiophen-3-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;dd)3-(Benzofuran-5-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;ee)6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine;ff)3-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;gg)3-Morpholin-4-ylmethyl-6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine;hh)1-Morpholin-4-yl-2-[6-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-imidazo[1,2-a]pyridin-3-yl]-ethanone;ii)6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylicacid; jj)6-[2-(Pyridin-2-yl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-imidazo[1,2-a]pyridine;kk)1-Morpholin-4-yl-2-[6-(2-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-imidazo[1,2-a]pyridin-2-yl]-ethanone;ll)6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylicacid (2-dimethylamino-ethyl)-amide; mm)6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylicacid ethyl ester; nn)6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylicacid amide; oo)8-Fluoro-6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine;pp)[6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine;qq)N-[6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridin-3-yl]-acetamide;rr)6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylicAcid Amide; ss)6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-2-carboxylicAcid (2-Dimethylamino-ethyl)-amide; tt)6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylicAcid Amide; uu)7-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine;vv)3-(4-Chloro-phenyl)-6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b)pyrazol-3-yl]-imidazo[1,2-a]pyridine;ww)5-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole;xx)1-Methyl-6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole;yy)1-Methyl-6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole;zz)1-Methyl-5-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole;aaa)1-Methyl-5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole;bbb)5-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole;ccc)6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole;ddd)5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole;eee)6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-[3-(tetrahydro-pyran-2-yloxy)-propyl]-1H-benzoimidazole;fff)2-{7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrido[2,3-b]pyrazin-2-yloxy}-ethanol(Ex. 55a) ggg)7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-quinoxalin-2-one;hhh)3-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl][1,5]naphthyridine(Ex. 55c) iii) 3-[6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propan-1-ol; jjj)3-[6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propan-1-ol;kkk) Methanesulfonic Acid3-[6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propylEster; lll) Methanesulfonic acid3-[6-[2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propylester (Ex. 57b) mmm)Dimethyl-[3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazol-1-yl]propyl]amine;nnn)Diethyl-[3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazol-1-yl]propyl]amine;ooo)6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-(3-morpholin-4-yl-propyl)-1H-benzoimidazole;ppp)6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-(3-pyrrolidin-1-yl-propyl)-1H-benzoimidazole;qqq)6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1-(3-piperidin-1-yl-propyl)-1H-benzoimidazole;rrr)5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-benzoimidazole;sss)6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline;ttt)2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline;uuu)2-[7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalin-2-yloxy]-ethanol;vvv)4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,6]naphthyridine;www)6-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-isoquinoline;xxx)6-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole;yyy)2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazole;zzz)5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzothiazol-2-ylamine;aaaa)4-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole;bbbb)3-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-indole;cccc)3-(2,3-Dihydro-benzofuran-5-yl)-2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;dddd) Acetic acid5-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzofuran-3-ylester; eeee)3-(5-Methoxy-benzofuran-3-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;ffff)5-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzofuran-2-carboxylicacid; gggg)3-(Benzofuran-2-yl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole;hhhh)5-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine;iiii)5-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-pyrazolo[1,5-a]pyrimidine;jjjj)5-[2-(Pyridin-2-yl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl]-pyrazolo[1,5-a]pyrimidine;kkkk)8-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-[1,6]naphthyridine;llll)3-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-pyrazolo[1,5-a]pyrimidine;mmmm)2-[2-(Pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-[1,5]naphthyridine;nnnn)2-Chloro-7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline;oooo)Dimethyl-(2-{7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalin-2-yloxy}-ethyl)-amine;pppp)Dimethyl-(2-{7-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxalin-2-yloxy}-propyl)-amine;qqqq)7-[2-(6-Methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoxaline-2-carboxylicacid amide; or a pharmaceutically acceptable salt thereof.